{60 -{8 1-benzoyl-3r-alkyl-4(r)-piperidylmethyl{9 {62 -oxo-{62 (6,7 substituted-4 quinolyl)propionic acid and racemates

ABSTRACT

Quinine, quinidine, their antipodes or racemates and derivatives thereof, are prepared by (a) cyclizing the correspondingly substituted 4-(3-(1-chloro-3(R)-alkyl(or alkenyl)- 4(R)piperidyl)-1-oxopropyl)quinolines, antipodes or racemates thereof, to the corresponding 4-(5(R)-alkyl(or alkenyl)-4(S)quinuclidin-2(S) or 2(R) ylcarbonyl)quinolines, antipodes or racemates thereof; and (b) stereoselectively reducing the products of step (a) to Alpha (S)-(5(R)-alkyl(or alkenyl)-4(S)quinuclidin-2(R)-yl)-4-quinolinemethanols, antipodes or racemates thereof, and Alpha (R)-(5(R)-alkyl(or alkenyl)-4(S)-quinuclidin2(S)-yl)-4-quinolinemethanols, antipodes or racemates thereof. Various intermediates and the end products are useful antimalarial and antiarrhythmic agents.

United States Patent [191 v Gutzwiller et al.

[ 1 Dec. 31, 11974 [75] Inventors: Juerg Albert Walter Gutzwiller,

Bettingen, Switzerland; Milan Radoje Uskokovic, Upper Montclair, NJ.

[73] Assignee: Hoffman-La Roche Inc., Nutley,

22 Filed: Apr. 26, 1973 21 Appl. NO.2 354,822

Related US. Application Data [52] 11.8. CI. 260/287 R, 260/284 R, 260/288 R,

260/293.88, 424/258 [51] Int. Cl C07d 43/24 [58] Field of Search 260/287 R, 284

[56] References Cited UNITED STATES PATENTS 8/1973 Gutzwiller et al. 260/284 11/1973 Gutzwiller et a1. 260/284 OTHER PUBLICATIONS Chemical Catalogue for Pfaltz and Bauer, lnc., pg. 184, MO D 55240.

March, Advanced Organic Chemistry," McGraw Hill Book Co., pp. 592-593.

Primary ExaminerDonald G. Daus Assistant Examiner-D. Wheeler Attorney, Agent, or FirmSamuel L. Welt; Bernard S. Leon; William G. lsgro [5 7 ABSTRACT Quinine, quinidine, their antipodes or racemates and derivatives thereof, are prepared by (a) cyclizing the correspondingly substituted 4-[3-(1-chloro-3(R)- alkyl(or alkenyl)- 4(R)-piperidyl)-1- oxopropyl]quinolines, antipodes or racemates thereof, to the corresponding 4-[5(R)-alkyl(or alkenyl)-4(S)- quinuclidin-2(S) or 2(R) ylcarbonyl]quinolines, antipodes or racemates thereof; and (b) stereoselectively reducing the products of step (a) to oz(S)-[5(R)- alkyl(or alkenyl)-4(S)- quinuclidin-2(R)-yl]-4- quinolinemethanols, antipodes or racemates thereof, and a(R)-[5(R)-alkyl(or alkenyl)-4(S)-quinuclidin- 2(S)-yl]-4-quinolinemethanols, antipodes or racemates thereof. Various intermediates and the end products are useful antimalarial and antiarrhythmic agents.

9 Claims, No Drawings 1 a-[l-BENZOYlL-3R-ALKYL-4(R)-PIPERII)YLME- 'rnYt g gggo-prsq SUBSTITUTED-4 QUINOLYMPROPIONIC ACID AND RACEMATES CROSS-REFERENCE TO RELATED APPLICATIONS This is a division of application Ser. No. 212,648, now U.S. Pat. No. 3,753,992, filed Dec. 27, 1971, which in turn is a continuation-in-part of application Ser. No. 104,785, filed Jan. 7, 1971, now abandoned, which is a continuation in part of application Ser. No. 837,304, filed June 27, 1969,-now abandoned, which in turn is a continuation-in-part of application Ser. No. 741,913, filed July 2, 1968, now abandoned.

SUMMARY OF THE INVENTION The invention relates to a process for preparing quinine, quinidine and derivatives thereof which is exemplified by the following reaction scheme:

R2 H R2 H N-H N-C Chlorination o f om fi (R9111 fi N III IV Cyclization l H i H N N H l (R0111 J l)m V VI i Reduction l Reduction R R2 A 2 1 1 OH H A 1 N 1 H 110? H (R1)m J (R0111 N/ I II antipodes and racemates thereof;

wherein m is 0, 1 or 2; R is hydrogen, hydroxy, halogen, lower alkyl, lower alkoxy, trifluoromethyl, or, when m is 2, R taken together with an adjacent R is also methylenedioxy; and R is lower alkyl or lower alkenyl.

In another aspect, the invention relates to compounds of the formulas antipodes and racemates thereof;

wherein n is l or 2; R is lower alkyl or lower alkcnyl; R is hydrogen, hydroxy, lower alkyl, lower alkoxy, trifluoromethyl, halogen, or, when n is 2, R taken together with an adjacent R is also methylenedioxy; when R is hydrogen, R is lower alkyl, trifluoromethyl or halogen; when R is other than hydrogen and n is 1, R is lower alkoxy, lower alkyl, hydrogen, trifluoromethyl, halogen, or taken together with an adjacent R is methylenedioxy; and when R is other than hydrogen and n is 2, R is hydrogen, and pharmaceutically acceptable acid addition salts thereof.

The compounds of Formulas 1c and [1c are useful antimalarial and antiarrhythmic agents.

In a further aspect, the invention relates to compounds of the formulas 2 w R and antipodes and racemates thereof;

wherein R R R and n are as previously described, and pharmaceutically' acceptable acid addition salts thereof.

The compounds of Formulas V0 and We are useful as intermediates and as antimalarial and antiarrhythmic agents.

In still a further aspect, the invention relates to compounds of the formulas antipodes and racemates thereof R1 II IF-H antipodes and racemates thereof; wherein R,, R R,,, R,,, m and n are as previously described, and R is lower alkyl.

The compounds of Formulas IXa, IIlc and IV are useful as intermediates in the process of the invention.

DETAILED DESCRIPTION OF THE INVENTION The term lower alkyl as used herein denotes a hydrocarbon group containing 1-7 carbon atoms, such as methyl, ethyl, propyl, butyl and the like; ethyl is preferred. The term lower alkoxy denotes a lower alkyl ether group in which the lower alkyl moiety is described as above. The term lower alkenyl as used herein denotes a hydrocarbon group containing 2-7 carbon atoms, such as vinyl, propenyl, butenyl and the like. Preferred is vinyl. The term hal0gen" denotes all of the halogens, i.e., bromine, chlorine, fluorine and iodine.

As is evident from the above R, or R,, or the like are individually selected from the various groupings hereinbefore described. Moreover, when m or n is 2, R, or R,, or the like can additionally form with an adjacent R, or R,, or the like the methylenedioxy radical. Thus, eith'erwhen m or n is l or 2, R, or R,, or the like can individually also represent hydrogen, hydroxy, halogen, lower alkyl, lower alkoxy or trifluoromethyl. Additionally, when m or n is 2, two adjacent groupings of R, or R,, can together represent methylenedioxy.

The process aspect of the invention is exemplified by Reaction Scheme l:

SCHEME l C hlorlnntion III Cyclization V VI l Reduction l) it H HOj Q I V II ably carried out at room temperature or above, preferably at a temperature between and 50C. Moreover, the chlorination can be suitably carried out in the presence of an inert organic solvent, for example, a hydrocarbon such as benzene, a halogenated hydrocarbon such as dichloromethane or chloroform, or an ether such as ether or dioxane.

The 4-[3-(l-chloro-3(R)-alkyl(or alkenyl)piperid- 4(R)-yl)-l-oxopropyl]quinolines of Formula lV, antipodes or racemates thereof, are converted to the corresponding epimeric 4-[5(R)-alkyl(or alkenyl)-4(S)- quinuclidin-2(R)-ylcarbonyl]qu inolines of Formula V, antipodes or racemates thereof, and 4-[5(R)-alkyl(or alkenyl)-4(S)-quinuclidin-2(S)-ylcarbonyl]quinolines of Formula Vl, antipodes or racemates thereof, under acidic conditions, utilizing a cyclizing agent. Exemplary of such agents are inorganic or organic acids such as mineral acids, for example, phosphoric acid and sulfuric acid; strong alkanoic acids, for example, trichloroacetic acid; and mixtures thereof, for example, acetic/- sulfuric acid. The reaction is conveniently carried out at room temperature or above, preferably at a temperature between 20C and 50C. Moreover, the cyclization can be suitably carried out in the presence of an inert solvent of the type previously described. As mentioned above, the cyclization yields a mixture of the epimeric compounds of Formulas V and VI, which can be reacted further as such or can be separated into the respective epimers utilizing methods such as crystallization, and the like, and such epimer reacted separately.

The conversion of the 4-[5(R)-alkyl(or alkenyl)- 4(S)-quinuclidin-2(R)-ylcarbonyl]quinolines of Formula V, antipodes or racemates thereof to a(S)-[5(R)- alkyl(or alkenyl)-4-(S)-quinuclidin-2(R)-yl]-4- quinolinemethanols of Formula I, antipodes or racemates thereof, respectively, is carried out utilizing a stereoselective reducing agent, for example, a dialkylaluminum hydride, such as diisobutylaluminum hydride or the like. The reduction is suitably carried out at room temperature; however, temperatures above or below room temperature may be employed. It is preferred to employ a temperature between 20C. and

50C. The reduction can be conveniently conducted in the presence of an inert organic solvent, for example, a hydrocarbon such as benzene or toluene, or an ether such as diethylether, tetrahydrofuran or the like.

The conversion of the compounds of Formula V or their racemates to those of Formula I, antipodes or racemates thereof, respectively, when R is lower alkyl, can also be effected utilizing a hydrogenation catalyst such as nickel, palladium, ruthenium, copper or barium chromite in the presence of a solvent, for example, an aqueous or non-aqueous alkanol such as methanol or ethanol, or an ether such as dioxane. When R is lower alkyl or lower alkenyl, the conversion can be effected utilizing a hydrogenation-agent such as aluminum in methanol, sodium isopropoxide in toluene, lithium aluminum hydride, aluminum hydride, chloroaluminum hydride, dichloroaluminum hydride, bromoaluminum hydride, dibromoaluminum hydride, lithium tritert.- butoxyaluminum hydride in ether, tetrahydrofuran, dioxane or the like.

The conversion of the 4-[5(R)-alkyl(or alkenyl)- 4(S)-quinuclidin-2(S)-ylcarbonyl]quinolines of Formula Vl, antipodes or racemates thereof, to the a(R)- [5(R)-alkyl(or alkenyl)-4(s)-quinuclidin-2(S)-yl]-4- quinolinemethanols of Formula ll, antipodes or racemates thereof, respectively, is carried out according to the procedures described for the conversion of the compounds of Formula V.

The 4-[3 -[3(R)-alkyl(or 'alkenyl)-piperid-4-(R)-yl]- 1-oxopropyl]-quinolines of Formula lll, antipodes or racemates thereof, can be cyclized to the 4-[5(R)- alkyl(or alkenyl)-4(S)-quinuclidin-2(R) (or 2(8))- ylcarbonyllquinolines of Formula VVl, antipodes or racemates thereof, respectively, according to the reacwherein R, is hydrogen, hydroxy, halogen, lower alkyl, lower alkoxy or trifluoromethyl, or, when m is 2, R, taken together with an adjacent R, may be also methylenedioxy; R is alkyl or lower alkenyl; m is 0, l or 2; and X is halogen.

In Reaction Scheme III, the N-halogenation of the compounds of Formula II], antipodes or racemates thereof, to the corresponding N-halo compounds of Formula lVc, antipodes or racemates thereof, is effected utilizing a halogenating agent, such as hypobromous acid, sodium hypochlorite, N-chlorosuccinimide, N-bromosuccinimide, N-bromoacetamide or the like, in an inert organic solvent, for example, an ether such as tetrahydrofuran, dioxane or the like; a chlorinated hydrocarbon such as methylene chloride, chloroform,

' car-bon tetrachloride, or the like; or an alkanol such as methanol, ethanol, or the like.

The cyclization of the N-halo compounds of Formula lVc. antipodes or racemates thereof, to the corresponding compounds of Formula V-VI, antipodes or racemates thereof, is conducted under basic conditions, for example, with sodium ethoxide in ethanol, sodium methoxide in methanol, or the like, or under strongly acidic conditions, for example, with sulfuric acid, phosphoric acid, trichloroacetic acid, trifluoroacetic acid, acetic acid/sulfuric acid mixture or the like.

When R in Formula III is lower alkyl, the cyclization of the compounds of Formula III to the corresponding compound of Formula V-Vl can also be conducted according to the reaction set forth in Scheme lV.

SCHEME IV III V-VI

ln-Reaction Scheme IV, the C-halogenation of the compounds of Formula Ill, antipodes or racemates thereof, to the corresponding compounds of Formula X, antipodes or racemates thereof, can be effected with a halogenating agent, for example, molecular halogen, such as chlorine or bromine in the presence of a hydrogen halide such as hydrogen chloride or hydrogen bromide in water, ether, acetic acid or other inert organic solvents. The cyclization ofthe compounds of Formula X, antipodes or racemates thereof, to the corresponding compounds of Formula V-Vl, antipodes or racemates thereof, is effected utilizing a sodium alkoxide such as sodium methoxide or sodium ethoxide, for example, in an alkanol such as methanol, ethanol, or the like.

When R in Formula lll is lower alkenyl, the cyclization can be effected according to the reaction set forth in Scheme V.

wherein R is lower alkyl.

wherein R is lower alkyl.

In Reaction Scheme V, the halogenation of the compounds of Formula llla, antipodes or racemates thereof, to the corresponding compounds of Formula Xa, antipodes or racemates thereof, is effected utilizing a halogenating agent, for example, molecular halogen, such as chlorine or bromine in the presence of a halogen halide, such as hydrogen chloride or hydrogen bromide in water, ether, acetic acid or other inert organic solvents. The cyclization of the compounds of Formula Xa, antipodes or racemates thereof, to the corresponding compounds of Formula Xl, antipodes or racemates thereof, is effected utilizing a sodium alkoxide such as sodium methoxide or sodium ethoxide in an alkanol such as methanol, ethanol or the like. The dehalogenation of the compounds of Formula XI, antipodes or racemates thereof, to the corresponding compounds of Formula V-VI, antipodes or racemates thereof, is effected with, for example, sodium iodide.

SCHEME la \N/ IIa antipodes or racemates thereof.

Reaction Scheme la represents a preferred embodiment of Reaction Scheme I, i.e., the preparation of dihydroquinidine and dihydroquinine, and is carried out utilizing the reaction conditions set forth for Reaction Scheme I. In Reaction Scheme la, dihydroquinotoxine of Formula Illa, antipode or racemate thereof, is converted to N-chloro-dihydroquinotoxine of Formula IVa, antipode or racemate thereof. The N- chloro-dihydroquinotoxine of Formula lVa, antipode or racemate thereof, is converted to the epimeric dihy- 3 droquinidinone of Formula Va, antipode or racemate thereof, and dihydroquinone of Formula Vla, antipode or racemate thereof, which are in turn converted to dihydroquinidine of Formula Ia, antipode or racematev thereof, and dihydroquinine of Formula Ila, antipode or racemate thereof, respectively.

CHaO

Reaction Scheme lb represents another preferred embodiment of Reaction Scheme I, i.e., the preparation of quinidine and quinine, antipodes or racemates thereof, and is carried out utilizing the reaction conditions set forth in Reaction Scheme I. In Reaction Scheme lb, quinotoxine of Formula lllb, antipode or racemate thereof, is converted to N-chloroquinotoxine of Formula lVb, antipode or racemate thereof. The N-chloroquinotoxine of Formula lVb, antipode or racemate thereof, is converted to quinidinone of Formula Vb, antipode or racemate thereof, and quininone of Formula Vlb, antipode or racemate thereof, which are in turn converted to quinidine of Formula Ib, antipode or racemate thereof, and quinine of Formula Ilb, antipode or racemate thereof, respectively.

SCHEME ll COORs OOR4 VIII Hydrolysis and Decarboxylation III antipodes or racemates thereof wherein R R and m are as previously described; and R and R are lower alkyl.

ln Reaction Scheme ll, the cinchoninic acid lower alkyl esters of Formula Vll, which are known or are analogs of known compounds readily obtained by known procedures, are reacted in the presence of a base, for example, alkaline metal alkoxides, such as sodium methoxide, sodium ethoxide, potassium tertiary butoxide and the like, with the l-benzoyl-3(R)-alkyl(or alkenyl)-4(R)-piperidinepropionic acid esters of Formula 'Vlll, antipodes or racemates thereof, which are known compounds or are analogs of known compounds readily obtained by known procedures, or by the procedure hereinafter described in Scheme III, to yield the corresponding a-[l-benzoyl-3(R)-alkyl(or alkenyl)- 4(R)-piperidylmethyl]-B-oxo-4-quinolinepropionic acid esters of Formula IX, antipodes or racemates thereof. The reaction is conveniently conducted at reflux temperatures; however, lower temperatures may also be employed. An inert solvent, for example, ethers such as tetrahydrofuran, dioxane and the like, may also be conveniently employed.

The conversion of the a-[1-benzoyl-3(R)-alkyl(or alkenyl)-4(R)-piperidyl-methyl]-B-oxo-4- quinolinepropionic acid esters of Formula [X to the corresponding 4-[3-(3(R)-alkyl(or alkenyl)-4(R)- piperidyl)-l-oxopropyllquinolines of Formula lll is effected utilizing a hydrolyzing agent such as hydrochloric acid at reflux temperatures. Conveniently, temperatures below reflux may also be utilized.

The preparation of the l-benzoyl-3-(R)-alkenyl- 4(R)-piperidinepropionic acid esters of Formula Vlll, antipodes or racemates thereof, can be carried out as set forth in Reaction Scheme 11].

SCHEME II] cooR5 COORs l \QCHK (1 n on: \N/ \N in XII XIII COOR5 000115 H..- N Hp.- N

l Juan J'HIII N N Il-A 0 Unlln XlV XV COORs COORs XVI VIIIa wherein R is as previously described, and A is an inorganic acid such as sulfuric acid, phosphoric acid and the like, or organic acids, for example, lower alkanoic acids such as acetic acid, and the like, halogenated lower alkanoic acids such as trifluoroacetic acid, trichloroacetic acid and the like.

In Reaction Scheme III, the 3(R)-ethyl-4(R)- piperidinepropionic acid esters of Formula Xll, antipodes or racemates thereof, which are known compounds, are converted to the corresponding l'chloro- 3(R)-ethyl-4(R)-piperidine propionic acid esters of Formula Xlll, antipodes or racemates thereof, by utilizing a chlorinating agent, for example, N- chlorosuccinimide, N-chloroacetamide, alkali metal hypochlorite such as sodium hypochlorite and the like. The reaction is conducted in an inert organic solvent, for example, a hydrocarbon such as benzene, a halogenated hydrocarbon such as dichloromethane, an alkanol such as methanol, ethanol and the like, an ether such as diethylether, dioxane, tetrahydrofuran and the like. The reaction temperature is not critical; however, preferably, it is in the range of about 0C. and about room temperature.

The conversion of the compounds of Formula Xlll, their antipodes or racemates, to the corresponding 3 (R)-(2-chloroethyl)-4(R)-piperidinepropionic acid ester salts of the Formula XIV, antipodes or racemates thereof, is effected by irridiation with ultraviolet light source such as a 20OW-Hannovia high pressure mercury lamp in an acid such as previously described. The reaction temperature is not critical; however, preferably it is in the range of about 0C. to about room temperature.

The conversion of the compounds of Formula XlV, antipodes or racemates thereof, to corresponding 1- benzoyl-3(R)-(2-chloroethyl)-4(R)- piperidinepropionic acid esters of Formula XV, antipodes or racemates thereof, is effected utilizing a benzoyl halide such as benzoyl chloride, in an inert organic solvent, for example, a hydrocarbon such as benzene, toluene and the like, a halogenated hydrocarbon such as dichloromethane, chloroform and the like, or ethers such as diethyl ethers, tetrahydrofuran, dioxane and the like. The pH of the reaction mixture is maintained between about 6 to about 9 utilizing, for example, alkali metal carbonates such as sodium or potassium carbonate. The reaction temperature is not critical; however, preferably it is in the range of about 0C. and about room temperature.

The conversion of the compounds of Formula XV, antipodes or racemates thereof, to the corresponding l-henzoyl-3(R)-(2-iodocthyl)-4(R)- piperidinepropionic acid esters: of the Formula XVI.

. bly it is in the range of about C. and about the reflux of the reaction mixture.

The conversion of the compounds of Formula XVl. antipodes or racemates thereof, to the corresponding l-benzoyl-3(R)-vinyl-4(R)-piperidinepropionic acid esters of the Formula Vllla, antipodes or racemates thereof, is effected utilizing an organic base, for example, pyridine, B-collidine, dimethylformamide and the like. Advantageously, an inorganic salt, for example, lithium bromide, lithium chloride,- lithium carbonate, silver fluoride, silver carbonate and the like, may be utilized in the reaction. The reaction temperature is not critical; however, preferably it is in the range of about room temperature and about the reflux temperature of the reaction mixture.

The conversion of the compounds of Formula XV, antipodes or racemates thereof, to the corresponding l-benzoyl-3(R)-vinyl-4(R)-piperidinepropionic acid esters of the Formula VIIla, antipodes or racemates thereof, is effected by pyrrolysis, preferably at a temperature in the range of 150C. and about 250C. The reaction can be conducted at atmospheric pressure; however, preferably is conducted at reduced pressure, for example, in the range of about 0.1 mm/Hg to 0.0l mm/Hg.

In another aspect, the invention relates to compounds of the formulas wherein n is l or 2; R is lower alkyl or lower alkenyl; R is hydrogen, hydroxy, lower alkyl, lower alkoxy, trifluoromethyl or halogen, or, when n is 2, R taken together with an adjacent R is also methylenedioxy; when R is hydrogen, R is lower alkyl, trifluoromethyl or halogen; when R is other than hydrogen and n is 1, R is lower alkoxy, lower alkyl, hydrogen, trifluoromethyl or halogen, or taken together with an adjacent R is also methylenedioxy; and when R is other than hydrogen and n is 2, R is hydrogen, and pharmaceutically acceptable acid addition salts thereof.

Exemplary of the compounds of Formulas lc and llc are:

7-Methoxy-a-(S)-[5(R)-ethyl-4(S)-quinuclidin- 2(R)-yl]-4-quinolinemethanol [hereinafter referred to as 7-methoxy-dihydrocinchonine], its antipode and racemic analog;

7-Methoxy-a(R)-[5(R)-ethyl-4(S)-quinuclidin-2(S)- yll-4-quinolinemethanol [hereinafter referred to as 7'-methoxy-dihydrocinchonidine], its antipode and racemic analog; 6,7-Dimethoxy-a(S)-[5(R)-ethyl-4(S)-quinuclidin- 2(R)-yl-]-4-quinolinemethanol [hereinafter referred to 6,7-dimethoxy-dihydrocinchonincl, its antipode and racemic analog; 6,8-Dimethoxy-a(S)-[5(R)-ethyl-4(S)-quinuclidin- 2(R)-yll-4-quinolinemethanol, its antipode and racemic analog; 6,7-Dimethoxy-a(R)-[5(R)-ethyl-4(S)-quinuclidin- 2(S)-yl]-4-quinolinemethanol [hereinafter referred to as 6',7-dimethoxy-dihydrocinchonidine], its antipode and racemic analog; 6,8-Dimethoxy-a(R)-[5(R)-ethyl-4(S)-quinuclidin- 2(S)-yl]-4-quinolinemethanol, its antipode and racemic analog; 6-Methoxy-a(S)-[5( R)-propyl-4(S)-quinuclidin- 2(R)-yl]-4-quinolinemethanol, antipode and racemic analog; 6-Methoxy-a (R)-[5(R)-allyl-4(S)-quinuclidin-2(S)- yl]-4-quinolinemethanol, antipode and racemic analog; 6-Methyl-a(S)-[5(R)-ethyl-4(S)-quinuclidin-2(R)- yll-4-quinolinemethanol [hereinafter referred to as 6'-methyldihydrocinchonine1, its antipode and racemic analog; 6-Methyl-a(R)-5(R)-ethyl-4(S)-quinuclidin-2(S)- yl]-4-quinolinemethanol [hereinafter referred to as 6'-methyl-dihydrocinchonidine], its antipode and racemic analog; 6-Chloro-a(S)-[5(R)-ethyl-4(S)-quinuclidin-2(R)- yl]-4-quinolinemethanol [hereinafter referred to as 6-chloro-dihydrocinchonine], its antipode and racemic analog; 6-Chl0ro-a(R)-[5(R)-ethyl-4(S)-quinuclidin-2(S)- yl]-4-quinolinemethanol [hereinafter referred to as 6'-chloro-dihydrocinchonidinel, its antipode and racemic analog; 7-Chloro-oz(S)-[5(R)-ethyl-4(S)-quinuclidin-2(R)- yl]-4-quinolinemethanol [hereinafter referred to as 7'-chloro-dihydrocinchonine], its antipode and racemic analog; 7-Chloro-a(R)-[5(R)-ethyl-4(S)-quinuclidin-2(S)- yl]-4-quinolinemethanol [hereinafter referred to as 7'-chloro-dihydrocinchonidine], its antipode and racemic analog; 7-Chloro-a-(S)-[5(R)-vinyl-4(S)-quinuclidin-2(R)- yl]-4-quinolinemethanol [hereinafter referred to as 7'-chloro-cinchonine], its antipode and racemic analog; 7-Chloro-a(R)-[5(R)-vinyl-4(S)-quinuclidin-2(S)- yll-4-quinolinemethanol [hereinafter referred to as 7'-chloro-cinchonidine], its antipode and racemic analog; 6,7-Methylenedioxy-ot(S)-[5(R)-vinyl-4(S)- quinuclidin-2(R)-yl]-4-quinolinemethanol [hereinafter referred to as 6,7-methylenedioxycinchonine], its antipode and racemic analog; 6,7-Methylenedioxy-a(R)-[5(R)-vinyl-4(S)- quinuclidin-2(S)-yl[-4--quinolinemethanol [hereinafter referred to as 6',7'-methylenedioxycinchonidine], its antipode and racemic analog; 6-Chloro-a(S)-[5(R)-vinyl-4(S)-quinuclidin-2(R)- yl]-4-quinolinemethanol [hereinafter referred to as 6-chloro-einchonine], its antipode and racemic analog; 6-Chloro-a(R)-[5(R)-vinyl-4(S)-quinuclidin-2(S)- yll-4-quinolinemethanol [hereinafter referred to as 6-chloro-cinchonidine], its antipode and racemic analog; 6,8-Dichloro-a(S)-[5(R)-vinyl-4(S)-quinuclidin- 2(R)-yl[-4-quinolinemethanol [hereinafter referred to as 6,8'-dichloro-cinchonine], its antipode and racemic analog; 6,8-Dichloro-a(R)-[5(R)-viny|-4(S)-quinuclidin- 2(S)-yl]-4-quinolinemethanol [hereinafter referred to as 6',8-dichloro-cinchonidine], its antipode and racemic analog; 6,7-Methylenedixoy-a(S)-[5(R)-ethyl-4(S)- quinuclidin-2(R)-yl[-4-quinolinemethanol [hereinafter referred to as 6,7'-methylenedioxydihydrocinchonine], its antipode and racemic ana- 6,7-Methylenedioxy-a(R)-[5(R)-ethyl-4(S)- quinuclidin-2(S)-yl]-4-quinolinemethanol [hereinafter referred to as 6,7'-methylenedioxydihydrocinchonidine], its antipode and racemic analog; 7-Trifluoromethyl-a(S)-[5(R)-ethyl-4(S)- quinuclidin-2(R)-yl[-4-quinolinemethanol [hereinafter referred to as 7-trifluoromethyldihydrocinchonine], its antipode and racemic analog; 7-Trifluoromethyl-a(R)-[5(R)-ethyl-4(S)- quinuclidin-2(S)-yll-4-quinolinemethanol [hereinafter referred to as 7-trifluoromethyldihydrocinchonidine], its antipode and racemic analog; 6,8-Dichloro-a(S)-[5(R)-ethyl-4(S)-quinuclidin- 2(R)-yll4-quinolinemethanol [hereinafter referred to as 6',8-dichlorodihydrocinchonine1, its antipode and racemic analog; 6,8-Dichloro-a(R)-[5(R)-ethyl-4(S)-quinuclidin- 2(S)-yl]-4-quinolinemethanol [hereinafter referred to as 6,8'-dichlorodihydrocinchonidine], its antipode and racemic analog. 7-Trifluoromethyl-a(5)-[5(R)-vinyl-4(S)- quinuclidin 2(R)-yl]-4-quinolinemethanol [hereinafter referred to as 7-trifluoromethylcinchonine1, its antipode and racemic analog; 7-Trifluoromethyl-a(R)-[5(R)-vinyl-4(S)- quinuclidin-2(S)-yl[-4-quinolinemethanol [hereinafter referred to as 7'-trifluoromethylcinchonidine], its antipode and racemic analog; 5-Trifluoromethyl-a(S)-[5(R)-vinyl-4(S)- quinuc|idin-2(R)-yll-4-quinolinemethanol [hereinafter referred to as 5-trifluoromethylcinchonine1, its antipode and racemic analog; 5-Tril'luoromethyl-MR)-l5(R)-viuyl-4(S)- quinuclidin-2(S)-yl]-4-quinolinemethanol [hereinafter referred to as 5'-trifluoromethylcinehonidine1. its antipode and racemic analog;

6-Trifluoromethyl-a(S)-[5(R)-vinyl-4(S)- quinuclidin-2(R)-yl]-4-quinolinemethanol [hereinafter referred to as 6'-trifluoromethylcinchonine], its antipode and racemic analog;

6-Trifluoromethyl-a(R)-[5(R)-vinyl-4(S)- quinuclidin-2(S)-yl]-4-quinolinemethanol [hereinafter referred to as 6-trifluoromethylcinchonidine], its antipode and racemic analog. In a further aspect, the invention relates to compounds of the formulas R R2 i \H I i I H O: 1 N/ 1 R and It; i (Rn)n A I J Um)" A Vc \"lt:

wherein R R R and n are as previously described, and pharmaceutically acceptable acid addition salts thereof.

Exemplary of the compounds of Formulas Vc and Vlc are:

7-Methoxy4-[5(R)-ethyl-4(S)-quinuclidin-2(R)- ylcarbonyl]-quinoline [hereinafter referred to as 7-methoxydihydrocinchoninone], its antipode and racemic analog; 7-MethoXy-4-[5(R)-ethyl-4(S)-quinuclidin-2(S)- ylcarbonyl]-quinoline [hereinafter referred to as 7'-methoxydihydrocinchonidinone], its antipode and racemic analog; 6,7-Dimethoxy-4-[5(R)-ethyl-4(S)-quinuclidin- 2(R)-yl-carbonyl[quinoline [hereinafter referred to as 6',7-dimethoxy-dihydrocinchoninone], its antipode and racemic analog; 6,8-Dimethoxy-4-[5(R)-ethyl-4(S)-quinuclidin- 2(R)-ylcarbonyllquinoline. its antipode and racemic analog; 6,7-Dimethoxy-4-[5(R)-ethyl-4(S)-quinuclidin 2(S)-ylcarbonyl]quinoline [hereinafter referred to as 6',7'-dimethoxy-dihydrocinchonidinone], its antipode and racemic analog; 6,8-Dimethoxy-4-[5(R)-ethyl4(S)-quinuclidin- 2(S)-ylcarbonyl]quinoline, its antipode and racemic analog; 6-Methyl-4-[5(R)-ethyl-4(S)-quinuclidin-2(R)- ylearbonyll-quinoline [hereinafter referred to as 6'-methyl-dihydrocinchoninone1, its antipode and racemic analog; 6-Methyl-4-[5(R)-ethyl-4(S)-quinuclidin-2(S)- ylcarbonyll-quinoline [hereinafter referred to as 6'-methyldihydrocinchonidinone], its antipode and racemic analog; 6-Chloro-4-[5(R)-ethyl-4(S)-quinuclidin-2(R)- ylcarbonyll-quinoline [hereinafter referred to as 6-chlorodihydrocinchoninone1, its antipode and racemic analog; 6-Chloro-4-l5(R)-ethyl-4(S)-quinuclidin-2(S)- ylcarhonyll-quinoline [hereinafter referred to as 6'-chlorodihydrocinchonidinone], its antipode and racemic analog; 7-Chloro-4-[5(R)-ethyl-4(S)-quinuclidin-2(R)- ylcarbonyl]-quinoline [hereinafter referred to as 7'-chlorodihydrocinchoninone], its antipode and racemic analog; 7-Chloro-4-[5(R)-ethyl-4(S)-quinuclidin-2(S)- ylcarbonyll-quinoline [hereinafter referred to as 7-chlorodihydrocinchonidinone1, its antipode and racemic analog; 7-Chloro-4-[5(R)rvinyl-4(S)-quinuclidin-2(R)- ylcarbonyll-quinoline [hereinafter referred to as 7-chlorocinchoninone], its antipode and racemic analog; 7-Chlor0-4-[5(R)-vinyl-4(S)-quinuclidin-2(S)- ylcarbonyl1-quinoline [hereinafter referred to as 7-chlorocinchonidinone], its antipode and racemic analog; and the like. 6,7-Methylenedixy-4-[5(R)-vinyl-4(S)-quinuclidin- 2(R)-yl carbonyll-quinoline [hereinafter referred to as 6,7-methylenedioxy-cinchoninone] its antipode and racemic analog; 6,7-Methylenedioxy-4-[5(R)-vinyl-4(S)-quinuclidin- 2(S)-yl carbonyl]-quinoline [hereinafter referred to as 6',7'-methylenedioxy-cinchonidinone] its antipode and racemic analog; 6,7-Methylenedioxy-4-[5(R)-ethyl-4(S)-quinuclidin- 2(R)-yl carbonyll-quinoline [hereinafter referred to as 6,7-methylenedioxy-dihydrocinchoninonel], its antipode and racemic analog; 6,7-Methylenedioxy-4[5(R)-ethyl-4(S)-quinuclidin- 2(S)-yl carbonyl]-quinoline [hereinafter referred to as 6,7-methylenedioxydihydrocinchonidinone], its antipode and racemic analog; 6,8-Dichloro-4-[5(R)-ethyl-4(S)-quinuclidin- 2(R)-yl carbonyl1-quinoline [hereinafter referred to as 6,8'-dichloro-dihydrocinchoninone], its antipode and racemic analog; 6,8-Dichloro-4-[5(R)-ethyl-4(S)-quinuclidin-2(S)-yl carbonyll-quinoline [hereinafter referred to as 6',--

8'-dichlorodihydrocinchonidinonel, its antipode and racemic analog; 6-Chloro-4-[5(R)-vinyl-4(S)-quinuclidin-2(R)- ylcarbonyl]-quinoline [hereinafter referred to as 6chlorocinchonin0ne], its antipode and racemic analog; 6-Chloro-4-[5(R)-vinyl-4(S)-quinuclidin-2(S)- ylcarbonyll-quinoline [hereinafter referred to as 6-chlorocinchonidinonel], its antipode and racemic analog; 7-Trifluoromethyl-4-[5(R)-ethyl-4(S)-quinuclidin- 2(S)-ylcarbonyl]-quinoline [hereinafter referred to as 7-trifluoromethyl-dihydrocinchonidinone], its antipode and racemic analog; 7-Trifluoromethyl-4-[5(R)-ethyl-4(S)-quinuclidin- 2(R)-ylcarbonyl]-quinoline [hereinafter referred to as 7-trifluoromethyl-dihydrocinchoninonel, its antipode and racemic analog; 6,8-Dichloro-4-[5(R)-vinyl-4(S)-quinuclidin-2(R)- ylcarbonyll-quinoline [hereinafter referred to as 6,8-dichlorocinchonin0ne], its antipode and racemic analog; 6,8-Dichloro-4'[5(R)-vinyl-4(S)-quinuclidin-2(S)- ylcarbonyll-quinoline [hereinafter referred to as 6,8-dichl0rocinchonidinone1, its antipode and racemic analog. In a still further aspect, the invention relates to compounds of the formulas wherein R R R R R m and n are as previously described.

Exemplary of the compounds of Formulas lXa, lllc and IV are:

a-[ l-Benzoyl-3(R)'vinyl-4(R)-piperidyl-methyl[-fioxo-B-(6,7-methylenedioxy-4quinolyl)propionic acid ethyl ester, its antipode and racemic analog; a-[ lBenzoyl-3( R)-ethyl-4(R )-piperidylmethyl]-B- oxo-B-(7-methoxy-4-quinolyl)propionic acid ethyl ester, its antipode and racemic analog;

a-[1-Benzoyl-3(R)-ethyl-4(R)-piperidylmethyll-B- oxo-B-(6,7-dimethoxy-4-quinolyl)propionic acid ethyl ester, its antipode and racemic analog;

a-[1-Benzoyl-3(R)-ethyl-4(R)-piperidylmethyl]-B- oxo-B-(6,8-dimethoxy-4-quinolyl)propionic acid ethyl ester, its antipode and racemic analog;

a-[ l-Benzoyl-3(R)-ethyl-4(R)-piperidylmethyl]-B- oxo-B-(6-methyl-4-quinolyl)propionic acid ethyl ester, its antipode and racemic analog;

a-[1-Benzoyl-3(R)-ethyl-4(R)-piperidylmethyl]-B- oxo-B-(6-chloro-4-quinolyl)propionic acid ethyl ester, its antipode and racemic analog;

or-[ l-Benzoyl-3(R)-ethyl-4(R)-piperidylmethyl]-B- oxo-B-(7-chloro-4-quinolyl)propionic acid ethyl ester, its antipode and racemic analog;

a-[ l-Benzoyl-3(R)-vinyl-4( R)-piperitlylmethyl]-B- oxo-B-(7-chloro-4-quinolyl)propionic acid ethyl ester, its antipode and racemic analog;

7-Methoxy-4-[3-(3(R)-ethyl-4(R)-piperidyl)-loxopropyH-quinoline [hereinafter referred to as 7'-methoxy-dihydrocinchotoxine], its antipode and racemic analog;

6,7-Dimethoxy-4-[3-(3(R)-ethyl-4(R)-piperidyl)-loxopropyll-quinoline [hereinafter referred to as 6,7'-dimethoxydihydrocinchotoxineI, its antipode and racemic analog;

6,8-Dimethoxy-4-[3-(3(R)-ethyl-4(R)-piperidyl-loxopropyll-quinoline, its antipode and racemic analog;

6-Methyl-4-l 3-( 3R )-cthyl-4( R )-piperidyl l oxopropyll-quinoline [hereinafter referred to as 6-methyl-dihydrocinchotoxine], its antipode and racemic analog;

6-Chloro-4-[3-(3R)-ethyl-4(R)-piperidyl)-loxopropyllquinoline [hereinafter referred to as 6'- chlorodihydrocinchotoxine], its antipode and racemic analog;

7-Chloro-4-[3-(3R)-ethyl-4(R)-piperidyl)-loxopropyl]-quinoline [hereinafter referred to as 7'-chloro-dihydro-cinchotoxineI, its antipode and racemic analog;

7-Chloro-4-[3-(3R)-vinyl-4(R)-piperidyl)-loxopropyll-quinoline [hereinafter referred to as 7-chlorocinchotoxine], its antipode and racemic analog;

6,7-Methylenedioxy-4[3-(3R)-vinyl-4(R)-piperidyll-oxopropyl]-quinoline [hereinafter referred to as 6,7-methylenedioxycinchotoxine], its antipode and racemic analog; 6-Methoxy-4-[ 3-( l-chloro-3(R)-ethyl-4(R)- piperidyl)-l-oxopropyl]quinoline [hereinafter referred to as N-chlorodihydroquinotoxine], its antipode and racemic analog;

7-Methoxy-4-[ 3-( l-chloro-3(R )-ethyl-4(R)- piperidyl)-l-oxopropyl]quinoline [hereinafter referred to as N-chloro-7'-methoxydihydrocinchotoxine], its antipode and racemic analog;

6,7-Methylenedioxy-4-[3-( l-chloro-3(R)-vinyl- 4(R)-piperidyl)-l-oxo-propyl1quinoline [hereinafter referred to as N-chlor-6,7- methylenedioxyquinotoxine], its antipode and racemic analog;

6-Chloro-4-[3-(l-chloro-3(R)-ethyl-4(R)- piperidyl)-l-oxopropyl]quinoline [hereinafter referred to as N-chloro-6'-chlorodihydrocinchotoxine], its antipode and racemic analog;

7-Chloro-4-[3-( l-chloro-3( R)-vinyl-4( R)-piperidyl)- l-oxopropyl1quinoline [hereinafter referred to as N-chloro-7'-chloro-cinchotoxine], its antipode and racemic analog;

7-Chloro-4-[ 3-( l-chloro-3( R)-ethyl-4(R)- piperidyl)-l-oxopropyl]-quinoline [hereinafter referred to as N-chloro-7-chlorodihydrocinchotoxine], its antipode and racemic analog.

Preferred compounds of Formulas lc, llc, lllc, Vc, Vlc and lXa are those wherein the fused benzo ring (hereinafter referred to as ring A) is substituted thusly:

Preferred compounds of Formula IV are those wherein ring A is The corresponding compounds of Formulas lo and llc above are characterized by the formulas wherein R is selected from the group consisting of methyl, C C lower alkyl and C -C lower alkenyl, the corresponding compounds of the Formulas Vc, Vlc, IXa and lllc wherein R is hydrogen; R is methoxy; R is methyl C -C -lower alkyl and C -C lower alkenyl can be similarly characterized, and pharmaceutically acceptable acid addition salts thereof.

Exemplary of such compounds are 6-methoxy-a(S)- [5(R)-propyl-4(S)-quinuclidin-2(R)-yl]-4- quinolinemethanol and racemic analog; o-methoxya(R)-[5(R)allyl-4(S)-quinuclidin-2(S)-yl]-4- quinoline-methanol and racemic analog; and the like.

The compounds of Formulas lc, llc, ld, lld, Vc and Vle and their pharmaceutically acceptable acid addition salts possess antimalarial and antiarrhythmic properties and are therefore useful as antimalarial and antiarrhythmic agents. Their pharmacologically useful antiarrhythmic activity is demonstrated in warm-blooded animals utilizing standard procedures, for example. the test compound is administered to prepared mongrel dogs. The chest cavity of the experimental animal previously anesthetized using a combination of sodium barbitol, 300 mg/kg. and pentobarbitol, 15 mg/kg, iv, is opened up through the third right interspace under artificial respiration and the pericardium is cut and sutured to the wall of the thorax so as to maintain the heart in a pericardial cradle throughout the course of the test procedure. Arterial pressure is monitored by inserting a polyethylene cannula into the aorta via the left carotid artery and is measured with an appropriate Statham pressure transducer. During the course of the experiment, electrical activity of the heart is viewed both on an oscilloscope and recorded on a Sanborn polyviso using standard ECG lead 11. The heart is also observed visually. The antiarrhythmic assay of the test drug is undertaken using a modification of the method of Scherf and Chick, Circulation, 3, 764-769 (1951). A dripping of 1 percent solution of acetylcholine is applied to the sinus node and the atrium is irritated by pinching with a pair of forceps. This procedure produces a continuous atrial arrhythmia which mostly consists of atrial fibrillation. Since hypokalemia produces a susceptibility to atrial fibrillation (Leveque, Arch. Int. Pharmacodyn, 149, 297-307,l964), 2 units/kg. of insulin is administered 30 minutes before the start of the acetylcholine drip. Once atrial fibrillation is established, there is a ten-minute waiting period before the test drug is administered. The test drugs are administered intravenously at the rate of 1 mg/kg/minute until normal sinus rhythm appears or until 30 mg/kg. of drug is administered.

When racemic 7'-methoxy-dihydrocinchonidinone is utilized as the test substance at a dosage of about 4.4 mg/kg, i.v., an antifibrillatory effect is observed for more than 60 minutes.

The pharmacologically useful antimalarial activity of the aforementioned compounds is demonstrated in warm-blooded animals using standard procedures, for example, the test substance is administered to albino mice in variable amounts. Albino mice are inoculated with about 10 million red cells infected with P. Bergei. Treatment is started on the first day after inoculation, and the drug is administered per os" during 4 consecutive days. On the seventh day of infection, smears are made, stained with giemsa and microscopically examined for P. Berghei.

When racemic 7'-methoxy-dihydrocinchonidine dihydrochloride and racemic 7-methoxydihydrocinchonine dihydrochloride are utilized as the test substance at dosages in the range of 125 mg/kg. to about 250 mg/kg., the microscopical examination of the blood smears is free of P. Berghei (negative). The compounds of Formulas lc, 11c, Vc and Vlc and the pharmaceutically acceptable acid addition salts have effects qualitatively similar, for example, to those of quinine and quinidine of known therapeutic uses and properties. Thus, the compounds of the invention demonstrate a pattern of activity associated with antimalarials and antiarrhythmics of known efficacy and safety.

The compounds of Formulas lc, 11c, 1d, 11d, Vc, and Vlc form acid addition salts and such salts are also within the scope of this invention. Thus, the aforementioned compounds form pharmaceutically acceptable addition salts with, for example, both pharmaceutically acceptable organic and inorganic acids, such as acetic acid, succinic acid, formic acid, methanesulfonic acid, p-toluene-sulfonic acid, hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid and the like.

The products of the invention can be incorporated into standard pharmaceutical dosage forms, for exam ple, they are useful for oral or parenteral-application with the usual pharmaceutical adjuvant materials, e.g., organic or inorganic inert carrier materials such as water, gelatin, lactose, starch, magnesium stearate. talc, vegetable oils, gums, polyalltyleneglycols, and the like.

The pharmaceutical preparations can be employed in a solid form, e.g., as tablets, troches, suppositories, capsules, or in liquid form, e.g., as solutions, suspensions or emulsions. The pharmaceutical adjuvant material can include preservatives, stabilizers, wetting or emulsifying agents, salts to change the osmotic pressure or to act as buffers. They can also contain other therapeutically active materials.

Furthermore, the compounds of the formulas 1c, 11c, Id and 11d can be utilized as flavoring agents in beverages in the same manner as quinine is now used for this purpose.

The quantity of active medicament which is present in any of the above-described dosage forms in variable. The frequency with which any such dosage form will be administered will vary, depending upon the quantity of active medicament present therein and the needs and requirements of the pharmacological situation.

Due to the possible different spatial arrangements of their atoms, it is to be understood that the compounds of this invention may be obtained in more than one possible stereoisomeric form. The novel compounds, as described and claimed, are intended to embrace all such isomeric forms. Accordingly, the examples included herein are to be understood as illustrative of particular mixtures of isomers or single isomers and not as limitations upon the scope of the invention. All temperatures are in degrees centigrade, unless otherwise mentioned.

EXAMPLE 1 Preparation of Dihydroquinidinone To a solution containing 1.5 g. ofdihydroquinotoxine in 120 ml. of methylene chloride were added 2.5 ml. of 17% aqueous NaOCl solution and the mixture was stirred 16 hours at 20, under nitrogen. The organic phase was separated, washed once with water, dried over anhydrous sodium sulfate, and evaporated. The crude N-chloro-dihydroquinotoxine (1.65 g.) was dis solved in 10 ml. of methylene chloride and added dropwise to ml. of phosphoric acid which was stirred vigorously; the viscous mixture was stirred at 20 for 4 hours. The mixture was cooled and made a1- kaline to a p1-1 10 with 6N aqueous sodium hydroxide; the alkaline aqueous phase was extracted thoroughly with chloroform, which was dried over anhydrous sodium sulfate, and evaporated to dryness. The crude product (1.49 g.) was chromatographed on a column of 50 g. of neutral alumina, activity 11; elution with methylene chloride yielded 1.1 g. (73%) of an amorphous mixture of dihydroquinidinone and dihydroquininone which was crystallized from ethanol to yield 930 mg. of dihydroquinidinone having a melting point of 102104 after recrystallization from ether; [041 71(c 1.1, ethanol; after equilibration in ethanolic solution for 18 hours at 20).

EXAMPLE 2 Preparation ofRacemic dihydroquininone and racemic dihydroquinidinone from racemic dihydroquinotoxine To a solution containing 14.8 g. of racemic dihydroquinotoxine in 100 m1. of chloroform were added 26 ml. of 17% aqueous sodium hypochlorite solution, and the mixture was agitated under nitrogen at 20 for 16 hours. The aqueous phase was separated and washed with methylene chloride. The organic phases were combined, washed with water, dried over anhydrous sodium sulfate and evaporated to dryness.

The crude racemic N-chloro-dihydroquinotoxine (about 15 g.) was dissolved in about 20 ml. of methyldihydrocinchotoxine from cis ene chloride and the concentrated solution was added dropwise to 120 ml. of 100% phosphoric acid which was cooled in an ice-bath and vigorously stirred for 4 hours; the cooled solution was made alkaline with 6N aqueous sodium hydroxide and extracted thoroughly with ether. The ethereal phase was dried over anhydrous potassium carbonate and evaporated to dryness.

The crude product (14 g.) was chromatographed on 500 g. of alumina, activity 11. Elution with methylene chloride containing to 1% of methanolyielded 10.1 g. of pure, crystalline mixture of racemic dihydroquininone and racemic dihydroquinidinone (68% yield from dihydroquinotoxine). Crystallization from petroleum ether yielded 8.09 g. of crystals in three crops. The first crop having a melting point of 89-95 was recrystallized four times from petroleum ether to yield racemie dihydroquininone having a melting point of 100104.

Recrystallization of the third crop having a melting point of 8082, from petroleum ether yielded about a 1:1 mixture of racemic dihydroquininone and racemic dihydroquinidinone having a melting point of 80-83.

EXAMPLE 3 Preparation of Quinidinone from Quinotoxine To a solution containing 1.804 g. of quinotoxine in 35 ml. of methylene chloride were added 6.4 ml. of about a 17% aqueous sodium hyprochlorite solution, and the mixture was stirred under nitrogen for 2 /2 hours at 20. The organic layer was separated, washed with water. dried over anhydrous sodium sulfate and evaporated to dryness. The curde N-chloroquinotoxine (1.927 g.) was dissolved in about 6 ml. of methylene chloride-acetic acid 4:1 and added dropwise with stirring to ml. of 99.5% phosphoric acid. The resulting viscous mixture was stirred at 020 for 2 hours. The reaction mixture was poured into 50 ml. of water. The aqueous phase was made alkaline with 6N sodium hydroxide and the temperature was allowed to rise to about 40. After 10 minutes, the aqueous alkaline phase was extracted thoroughly with methylene chloride; the organic phase was washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness. The crude product (1.714 g.) was chromatographed through 17 g. of neutralalumina, activity Il; elution with methylene chloride yielded 1.178 g. (66%) of a mixture of quinidinone and quininone. Crystallization from ether yielded 915 mg. (51%) of quinidinone which after recrystallization from ether had a melting point of 9810l; [a],, 72.6 (c 0.99, ethanol; after equilibration in ethanolic solution for 18 hours at 20).

EXAMPLE 4 racemic 7-Methoxyl-benzoyl-3-ethyl-4- piperidinepropionic acid ethyl ester and 7-methoxy-4- carbethoxy-quinoline A solution containing 25.4 g. of cis 1-benzoyl-3- ethyl-4-piperidinepropionic acid ethyl ester in 250 ml. of dry tetrahydrofuran was added dropwise (30 min.) to a gently refluxing mixture of 26.9 g. of potassium tbutoxide and 25.8 g. of 7-methoxy-4-carbethoxyquinoline in 400 ml. of dry tetrahydrofuran, in an atmosphere of dry nitrogen. The mixture was heated under gentle reflux for two hours, and the solvent was removed under reduced pressure. The residue was dissolved in 300 ml. of 0.5N sodium hydroxide, and was washed with benzene. The alkaline aqueous phase containing a-cis(1-benzoyl-3-ethyl-4-piperidylmethyl)-B- oxo-,8-(7-methoxy-4-quinolyl)propionic acid ethyl ester was acidified so that a 6N aqueous hydrochloric Preparation of acid solution was obtained, and the solution was heated under reflux for 21 hours. The cooled reaction mixture was made alkaline with 6N sodium hydroxide, and extracted thoroughly with ether. The ethereal extracts were dried over anhydrous potassium carbonate and concentrated to dryness.

The crude product (21.0 g.) was dissolved in a small volume of acetone and added to a solution containing 14.5 g. of dibenzoyl-d-tartaric acid in acetone. The precipitate was separated by filtration, the free bases of the mother liquors were purified by preparative tlc to yield racemic 7-methoxy-dihydrocinchotoxine. A sample of the neutral dibenzoyl-d-tartarate was recrystallized from methanol and had a melting point of l74175.5. The free base dl-7'-methoxy-dihydrocinchotoxine was obtained as a yellow oil.

EXAMPLE 5 Preparation of 71-Methoxy-dihydrocinchotoxine from N-benzoyl-homocincholoipone ethyl ester and 7-methoxy-4-carbethoxy quinoline.

A solution containing 4.14 g of N-benzoylhomocincholoipone ethyl ester in 40 ml. of dry tetrahydrofuran was added dropwise (20 min.) to a gently refluxing mixture of 4.98 g. of potassium t-butoxide and 4.74 g of 7-methoxy-4-carbethoxyquinoline in ml. of dry tetrahydrofuran in an atmosphere of dry nitrogen. The mixture was heated under gentle reflux for three hours,

then the solvent was removed by distillation under vacuum, and the cooled residue dissolved in ml. of 0.5N sodium hydroxide. The alkaline phase was washed with benzene and the benzene phases washed with 0.5N sodium hydroxide. The combined aqueous phases containing a-[ l-henzoyl-3( R)-ethyl- 4(R)piperidylmethyl]-B-oxo-B-(7-methoxy-4-quinolyl) propionic acid ethyl ester were acidified so that a 6N hydrochloric acid solution was obtained, and then heated under gentle reflux for 17 hours. The cooled reaction mixture was made alkaline with 6N sodium hydroxide and thoroughly extracted with ether. The ethereal extracts were dried over anhydrous potassium carbonate and evaporated to dryness. The crude product (3.30 g.) was dissolved in a small volume of acetone, and 1.7 g. of dibenzoyl-d-tartaric acid as a concentrated solution in acetone was added. Crystallization yielded 4.11 g. (54%) of 7-methoxydihydrocinchotoxine as its neutral dibenzoyl-d tartarate; having a melting point of 177-l 79 after re crystallization from chloroform-methanol; [M 396 [c 0.5, ethanol-chloroform (1:2)].

EXAMPLE 6 Preparation of 7'-Methoxy-dihydrocinchoninone and 7-methoxy-dihydrocinchonidinone from 7-methoxydihydrocinchotoxine To a solution containing 2.65 g. of 7'-methoxydihydrocinchotoxine in 100 ml. of chloroform were added 5 ml. of about a 17% aqueous sodium hypochlorite solution. The resulting mixture was stirred at 20 for 16 hours. The organic phase was separated, washed with water, dried over anhydrous sodium sulfate and evaporated. The crude N-chloro-7'-methoxydihydrocinchotoxine was dissolved in a minimal amount of chloroform and added dropwise to 15 m1. of 100% phosphoric acid with vigorous stirring. The resulting viscous mixture was stirred at 20 for 4 hours. Thereafter, it was made alkaline with 6N potassium hydroxide and the temperature of the alkaline phase was allowed to reach about 40. After 10 minutes, the aque ous phase was extracted thoroughly with ether. The

ethereal phase was dried over anhydrous potassium carbonate, and concentrated to dryness. The crude product (2.49 g.) was chromatographed on a column of 75 g. of neutral alumina, activity 11; elution with methylene chloride yielded 1.49 g. (56%) of a mixture of 7'rmethoxy-dihydrocinchoninone and 7-methoxydihydrocinchonidinone having a melting point of 103108 after recrystallization from petroleum ether, and a specific rotation of [a],, +16 (c 0.27, ethanol;

- after equilibration in ethanolic solution for 18 hours at 1n the like manner, the following analogs can be prepared:

A mixture of 7-chloro-4-[5(R)-ethyl-4(S)- quinuclidin-2(R)-ylcarbonyl]-quinoline and 7-chloro-4-[5(R)-ethyl-4(S)- quinuclidin-2(S)-ylcarbonyl]-quinoline, which is amorphous; its antipode, which is amorphous; and racemate thereof, having a m.p. of 124127;

A mixture of 7-chloro-4-[5(R)-vinyl-4(S)- quinuclidin-2(S)-ylcarbonyl]-quinoline and 7-chloro-4-[5(R)-vinyl-4(S)- quinuclidin-2(S)-ylcarbonyl]-quinoline, which is amorphous;

A mixture of racemic 7-trifluoromethyl-4-[5(R)- ethyl-4(S)-quinuclidin-2(R)-ylcarbonyl]-quinoline and racemic -trifluoromethyl-4-[5 R )-ethyl-4(S )-quinuclidin-2(S ylcarbonyll-quinolinej m.p. l06l 1 1.

EXAMPLE7 Preparation of racemic 7-methoxydihydrocinchonidinone and racemic 7-methoxydihydrocinch'oninone from racemic 7-meth0xydihydrocinchotoxine To a solution containing 20.6 g. of racemic 7- methoxy-dihydrocinchotoxine in 150 ml. of chloroform were added 55 ml. of about a 17% aqueous sodium hypochlorite solution, and the mixture was agitated for 16 hours at 20. The organic phase was separated, washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The crude racemic N-chloro-7'- methoxy-dihydrocinchotoxine was dissolved in a minimum volume of chloroform and added dropwise to 150 ml. of concentrated phosphoric acid at 20 with vigorous stirring. The resulting viscous mixture was stirred for 2 hours. The solution was cooled with ice, diluted with water, and made alkaline with 6N sodium hydroxide. During neutralization, the temperature was allowed to reach about 40. After about minutes, the alkaline aqueous phase was extracted thoroughly with ether and the ethereal phase was dried over anhydrous potassium carbonate and evaporated to dryness. The crude, crystalline product (20.4 g.) was dissolved in petroleum ether, leaving an insoluble, tarry residue of 3.4

g. Crystallization from the same solvent yielded 9.49 g. of racemic 7'-methoxy-dihydrocinchonidinone and 7.52 g. of an amorphous mixture of racemic 7'- methoxy-dihydrocinchoninone and racemic 7- methoxy-dihydrocinchonidinone (total yield 82%). After 2 recrystallizations from petroleum ether, racemic 7-methoxy-dihydrocinchonidinone had a melting point of 115118.

EXAMPLE 8 Preparation of Dihydroquinidinc from dihydroquinidinone To a solution containing 2.0 g. of dihydroquinidinone in 150 ml. of dry toluene, stirred at in an atmosphere of dry nitrogen, were added dropwise 4.8 ml. of a 25% solution of diisobutyl aluminum hydride in toluone. As soon as all the ketone was consumed, the reac tion was quenched by the addition of 3 ml. of watermethanol (1:1). The aluminum hydroxide which pre cipitated was separated by filtration and was washed thoroughly with benzene and methanol. The combined filtrates were evaporated to dryness. Crystallization of the residue from ethanol yielded 1.90 g. of dihydroquinidine (94% yield) in three crops which after recrystallization from ethanol had a melting point of 168-169"; [01],, 227.9 (c 0.896. ethanol).

EXAMPLE 9 Preparation of Dihydroquinidinc and dihydroquinine from a mixture of dihydroquinidinone and dihydroquininone A solution containing 1.25 g. of dihydroquinidinone in 50 ml. ofbenzene containing 0.5 ml. of methanol was maintained at 20 for 2 /2 days under nitrogen. The solution was evaporated to complete dryness under vacuum, and the residue was redissolved in benzene and again evaporated to dryness. The resulting oily residue was dissolved in 50 ml. of dry benzene, and 3'ml. of a 25% solution of di-isobutyl aluminum hydride in toluene were added dropwise with stirring under an atmosphere of dry nitrogen. The reaction was quenched after about 30 minutes by adding 10 ml. of watermethanol (1:1) and the mixture was stirred vigorously for 30 minutes. The benzene layer was decanted. The aqueous aluminum suspension was washed several times with benzene and the combined benzene phases were dried over anhydrous magnesium sulfate and evaporated to dryness. The crude product (1.25 g. of colorless foam) was a practically pure mixture of dihydroquinidine and dihydroquinine (about 1:1) as determined by thin layer chromatography; and a specific rotation [al 62.2 (c 1.64, ethanol). Crystallization from ethanol yielded 490 mg. of pure dihydroquinidine having a melting point of l67-169. Chromatographic separation from mother liquors gave 550 mp of dihydroquinine, m.p. 168l70, [011 137.5.

EXAMPLE 10 Preparation of racemic dihydroquinine from racemic dihydroquininone To a solution containing 1.0 g. of racemic dihydroquininone in ml. of dry benzene were added dropwise 2.5 ml. of a 25% solution ofdi-isobutyl aluminum hydride in toluene with stirring under an atmosphere of dry nitrogen. After about 30 minutes, the reaction was quenched by the addition of 2 ml. of methanol-water (1:1). The alumina which precipitated was separated by filtration, washed thoroughly with methanol, and the filtrate was evaporated to dryness. Crystallization of the crude product (1.003 g.) from acetone yielded 718 mg. of racemic dihydroquinine as its monohydrate, which after recrystallization from acetone had a melting point of 174177.

EXAMPLE 1 1 Preparation of Anhydrous d,l-dihydroquinine d,1-Dihydr0quinine monohydrate after repeated evaporation from a benzene solution yielded d,1-

dihydroquinine having a melting point of 172-l74.

EXAMPLE 12 Preparation of Racemic dihydroquinine sulfate A solution containing 5.253 g. of rid-dihydroquinine in 20 ml. of methanol and 16.1 ml. of 1N aqueous sulfuric acid was cooled at The precipitated crystals were separated by filtration, washed with acetone and dried at 60l50 mm for 20 hours. After additional drying at 80l0.0l mm, d,l-dihydroquinine sulfate was obtained, which contained 0.5 mole of water and had a melting point of 2lO-2l3.

EXAMPLE 13 Preparation of Racemic dihydroquinine and racemic dihydroquinidine from a mixture of racemic dihydroquininone and racemic dihydroquinidinone The reduction of 5.06 g. of a crystalline mixture of racemic dihydroquininone and dihydroquinidinone (melting point of 76-89) was carried out in dry benzene with di-isobutyl aluminum hydride according to the procedure described in Example 8. The methanol extracts (3.87 g. were crystallized from acetone to yield 3.14 g. (61%) of racemic dihydroquinine monohydrate in three crops. The benzene extracts (1.54 g.) were crystallized from a concentrated solution in ethanol to yield 579 mg. (11%) of racemic dihydroquinidine in four crops. Racemic dihydroquinidine: after recrystallization from ethanol had a melting point of l52l54.5.

EXAMPLE 14 Preparation of Racemic dihydroquinidine sulfate To 2.02 g. of d,l-dihydroquinidine in 25 ml. of absolute ehtanol were first added 6.2 ml. of 1N aqueous sulfuric acid, followed by m1. of water. The sulfate (2.03 g.) crystallized after the volume was evaporated to ml. After drying at 80l0.0l mm for 70 hours, the d,l-

dihydroquinidine SO, contained mole of water and had a melting point of 208-211.

EXAMPLE 15 Preparation of Quinidine from quinidinone To a solution containing 1.00 g. of quinidinone in 40 ml. of dry benzene were added dropwise 2.4 ml. of a 25% solution of di-isobutyl aluminum hydride in toluene. After stirring at 20 under an atmosphere of dry nitrogen, 10 ml. of water was added. The benzene layer was separated, dried over anhydrous magnesium sulfate, and evaporated to dryness. The crude, crystalline product (0.890 g.) was recrystallized from ethanol to yield 0.646 g. of crystalline quinidine having a melting point of l69l7l; [01],, 264.3 (c 0.98, ethanol).

In the like manner, the following can be prepared: 7- chloro-a(S)-[5(R)-vinyl-4(S)-quinuclidin-2(R)-yl]-4- quinolinemethanol which crystallized from ethanolacetone has a melting point of 247250, [011 196 (c 0.88, ethanol-methylene chloride 4:1); and 7- chloro-a(R)-[5(R)-vinyl-4(S)-quinuclidin- 2(S)-yl]-4-quinoline-methanol which crystallized from acetoneether, has a melting point of 165-169, [011 67 (c 0.90, ethanol);

7-Chloro-a(S)-[5(R)-ethyl-4(S)-quinuclidin-2(R)- yl]-4-quinolinemethanol which crystallized from ethanol-acetone has a melting point of 278-279 [01],, 159.7 (ethanol acidic acid 9:1).

6-Chloro-a(S)-[5(R)-ethyl-4(S)-quinuclidin-2(R)- yl]-4-quinolinemethanol, m.p. 98-.

6-Chloro-a(R)-[5(R)-ethyl-4(S)-quinuclidin-2(S)- yl]-4-quinolinemethanol, m.p. 196198.

Antipode of 7-ch1oro-a(S)-[5(R)-ethyl-4(S)- quinuclidin-2(R)-yll-4-quinolinemethanol, m.p. 278-280, and racemic analog, m.p. 251253.

28 7-Chloro-a(R)-[5(R)-ethyl-4(S)-quinuclidin-2(S)- yl]-4-quinolinemethanol, m.p. 2l8220, antipode, m.p. 224225, and racemic analog, m.p. 192-193. 6-Chloro-a(S)-[5(R)-vinyl-4(S)-quinuclidin-2(R)- yll-4-quinolinemethanol, m.p. l54155.

6-Chloro-a(R)-[5(R)-vinyl-4(S)-quinuclidin-2(S)- yll-4-quinolinemethanol, m.p. l93-194.

6,8-Dichloro-a(S)-[5(R)-vinyl-4(S)-quinuclidin- 2(R)-yl]-4-quinolinemethanol (dihydrochloride, m.p. 250 dec.)

6,8-Dichloro-a(R)-[5(R)-vinyl-4(S)-quinuclidin- 2(S)-yll-4-quinolinemethanol, m.p. l05-l08.

Racemic 7-trifluoromethyl-a(S)-[5(R)-ethyl-4(S)- quinuclidin-2( R)-yl]-4-quinolinemethanol, m.p. 218219.5.

Racemic 7-trifluoromethyl-a(R)-[5(R)-ethyl-4-(S)- quinuclidin-2(S)-yl]-4-quinolinemethanol, m.p. l-176.

7-Trifluoromethyl-a(S)-[5(R)-vinyl-4(S)quinuclidin-2(R)-yl]-4-quinolinemethanol, m.p. 228-229.

7-Trifluoromethyl-a('R)-[5(R)-vinyl-4(S)-quinuclidin-2(S)-yll-4-quinolinemethanol (dihydrochloride, m.p. 21 l-215).

7-Trifluoromethyl-a(S)-[5(R)-ethyl-4(S)-quinuclidin-2(R)-yll-4-quinolinemethanol, m.p. 227230.

7-Trifluoromethyl-a(R)-[5(R)-ethyl-4(S)-quinuclidin-2(S)-yl]-4-quinolinemethanol, m.p. l63-164.

5-Trifluoromethyl-a(S)-[5(R)-vinyl-4(S)-quinuclidin-2(R)-yl]-4-quinolinemethanol.

5-Trifluoromethyl-a(R)-[5(R)-vinyl-4(S)-quinuclidin-2(S)-yll-4-quinolinemethanol.

6-Trifluoromethyl-a(S)-[5(R)-vinyl-4(S)-quinuclidin-2(R)-yll-4-quinolinemethanol.

6-Trifluoromethyl-a(R)-[5(R)-vinyl-4(S)-quinucli din-2(S)-yl]-4-quinolinemethanol.

EXAMPLE 16 Preparation of 7'-Methoxy-dihydrocinchonine and 7'-methoxydihydrocinchonidine from a mixture of 7'- methoxy-dihydrocinchoninone and 7'-methoxydihydrocinchonidinone To a solution containing 1.46 g. of a mixture of 7-methoxydihydrocinchoninone and 7'-methoxydihydrocinchonidinone in 50 ml. of dry benzene, stirred under an atmosphere of dry nitrogen at 20, were added dropwise 3.75 ml. of a 25% solution of diisobutyl aluminum hydride in toluene. When all the ketone was consumed, 5 ml. of 50% aqueous methanol were added. The alumina which precipitated was separated by filtration, and washed thoroughly with benzene. The combined filtrates were dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was triturated with acetone, and crystallization yielded 7'-methoxy-dihydrocinchonine. After recrystallizations from chloroform-petroleum ether, 7'-methoxy-dihydrocinchonine had a melting point of 23l233; [01], l69.5 (c 1.00, ethanol). From the mother liquors, 7'-methoxy-dihydrocinchonidine was obtained by fractional crystallization from acetone. After recrystallization, 7'-methoxydihydrocinchonidine had a melting point of 162165; [011 80.3 (c 0.98, ethanol).

EXAMPLE 17 Preparation of Racemic 7-methoxydihydrocinchonidine from racemic 7-methoxydihydrocinchonidinone To a solution containing 2.32 g. of racemic 7'- methoxydihydrocinchonidinone (melting point 1l2-l 16) in 50 ml. of dry benzene were added dropwise 6.5 ml. of a 25% solution of diisobutyl aluminum hydride in toluene at under an atmosphere of dry nitrogen. After stirring for about 30 minutes at 20, 8 ml. of 50% aqueous methanol were added. The alumina which precipitated was separated by filtration and washed thoroughly with benzene. The filtrate was dried over anhydrous sodium sulfate and concentrated to dryness. The residue was triturated with ether and 1.78

g. of crystalline racemic 7'-methoxydihydrocinchonidine having a melting point of 155157 were collected.

EXAMPLE 18 Preparation of Racemic 7-methoxydihydrocinchonine and racemic 7-methoxydihydrocinchonidine from a mixture of racemic 7'-methoxy-dihydrocinchoninone and 7'-methoxydihydrocinchonidinone To a solution containing 2.52 g. of an amorphous mixture of racemic 7-methoxy-dihydrocinchoninone and racemic 7-methoxydihydrocinchonidinone in 50 ml. of'dry benzene, were added dropwise 7.2 ml. of a solution of di-isobutyl aluminum hydride in toluene at 20 under an atmosphere of dry nitrogen.'After stirring for about minutes at 20, 8 ml. of 50% aqueous methanol were added, the alumina which precipitated was separated by filtration and washed thoroughly with benzene. The filtrate was dried over anhydrous sodium sulfate and concentrated to dryness. The residue was triturated with acetone, and 1.01 g. of isomer, i.e., racemic 7-methoxy-dihydrocinchonine, were separated. It had a melting point of 217-219 after recrystallization from chloroform-acetone. From the mother liquors, 0.63 g. (25%) of the lower melting racemic 7-methoxy-dihydrocinchonidine was isolated.

EXAMPLE 19 Preparation of 6,7'-Dimethoxy-dihydrocinchotoxine from 6,7-dimethoxy-4-carbethoxy quinoline and Nbenzoylhomocincholoipon ethyl ester A solution containing 3.28 g. of N-benzoylhomocincholoipon ethyl ester in 30 ml. of dry tetrahydrofuran was added dropwise (30 min.) to a gently refluxing mixture of 3.13 g. of 6,7-dimethoxy-4-carbethoxyquinoline and 3.40 g. of potassium S-butoxide in 50 ml. of dry tetrahydrofuran in an atmosphere of dry nitrogen. The mixture was heated under reflux for an additional two hours and then the solvent was removed by distillation under reduced pressure. The cooled residue was dissolved in 75 ml. of 0.5N sodium hydroxide. The alkaline phase was washed with benzene and the benzene extracts were washed with 0.5N sodium hydroxide. The combined aqueous phase was acidified with concentrated hydrochloric acid, so that about a 6N hydrochloric acid solution was obtained, and heated under gentle reflux for 24 hours. The cold reaction mixture was made alkaline with 6N sodium hydroxide and was thoroughly extracted with ether. The ethereal extracts were dried over anhydrous potassium carbonate and evaporated to dryness. The crude product was dissolved in a small volume of acetone, and 0.805 g. of dibenzoyl-d-tartaric acid was added as a concentrated solution in acetone. Crystallization yielded 1.63 g. of 6,7-dimethoxydihydrocinchotoxine neutral dibenzoyl-d-tartarate, having a melting point of 161.5-163.5, after three recrystallizations from methylene chloride/acetone; [011 37.7 [c 1.02, chloroform-ethanol (2:1) 1.

EXAMPLE 20 Mixture of 6',7Dimethoxy-dihydrocinchoninone and 6',7-dimethoxy-dihydrocinchonidinone from 6',7- dimethoxydihydrocinchotoxine To a solution containing 1.42 g. of 6',7-dimethoxydihydrocinchotoxine in 50 m1. of chloroform was added 3.5 ml. of about 17% aqueous sodium hypochlorite, and the mixture was stirred at 20 for minutes. The organic phase was separated, washed with water. dried over anhydrous sodium sulfate and concentrated to a volume of 10 ml. The solution containing 6.7- dimethoxy-4[3-(1chloro-3(R)-ethyl-4(R)-piperidyl)- loxopropyl]-quinoline was added dropwise to 10 ml. of phosphoric acid, and the viscous mixture was stirred at 20 for 5 hours. The mixture was diluted with water, made alkaline with 6N potassium hydroxide while allowing the alkaline phase to reach about 40, and extracted thoroughly with ether. The ethereal phase was dried over anhydrous potassium carbonate and concentrated to dryness. The crude product was purified on preparative tlc plates [chloroformtriethylamine (9:1 to yield .794 g. of a pure, amorphous mixture (about 1:1) of 6 ,7-dimethoxydihydrocinchoninone and 6',7-dimethoxydihydrocinchonidinone.

EXAMPLE 21 6',7-Dimethoxy-dihydrocinchonine and 6,7'- dimethoxy-dihydrocinchonidine from a mixture of 6,- 7'-dimethoxydihydrocinchoninone and 6',7- dimathoxy-dihydrocinchonidinone To a solution containing 0.745 g. of a mixture of 6,7'-dimethoxy-dihydrocinchoninone and 6,7- dimethoxy-dihydrocinchonidinone in 20 ml. of dry benzene, which was stirred in an atmosphere of dry nitrogen at 20, were added dropwise 1.5 ml. of 25% diisobutyl aluminum hydride in toluene. After about 60 minutes, 5 mlpof water-methanol (2:3) mixture was added. The precipitated alumina was separated by filtration and washed thoroughly with benzene. The combined filtrates were dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was separated by preparative tlc (chloroformtriethylamine-methanol 85:10:5) into the two isomers 6',7'-dimethoxydihydrocinchonine and 6',7- dimethoxy-dihydrocinchonidine. The less polar 6,7- dimethoxy-dihydrocinchonine was crystallized from ether; and had a melting point of l161 18 after several recrystallizations from acetone; [01],, 182.2 (c 0.95, ethanol). The more polar 6',7'-dimethoxy/dihydrocinchonidine could not be crystallized; [01],, 87.3 (c 0.68, ethanol).

EXAMPLE 22 and 6,7

to a refluxing mixture of 36.5 g. of 6,7-dimethoxy-4- carbethoxyquinoline and 33.6 g. of potassium tbutoxide in 500 ml. of dry tetrahydrofuran under an atmosphere of dry nitrogen. The mixture was heated under reflux for two hours and the solvent was removed under reduced pressure. The cold residue was dissolved in 300 ml. of 0.5N sodium hydroxide and washed with four 60 ml. portions of benzene. The combined aqueous phases containing the B-ketoester were acidified with cone. HCl, whereby a 6N hydrochloric acid solution was obtained, and then heated under reflux for 24 hours. The reaction mixture was allowed to cool, made alkaline with 6N sodium hydroxide and extracted with ether. The ethereal extracts were dried over anhydrous potassium carbonate and evaporated to dryness to give 14.5 g. (40%) of amorphous racemic 6,7-dimethoxydihydrocinchotoxine.

EXAMPLE 23 Preparation of Racemic 6,7-Dimethoxydihydrocin- 4 chonidinone and Racemic 6',7-Dimethoxydihydrocinchoninone from Racemic 6,7'-Dimethoxydihydrocinchotoxine To a solution containing 14.5 g. of racemic 6',7-dimethoxydihydrocinchotoxine in 200 ml. of dichloromethane was added 25 ml. of about a 17% aqueous sodium hypochlorite, and the mixture was stirred vigorously for 60 min. The organic phase was separated, washed with water, dried over anhydrous sodium sulfate, and evaporated to a volume of about 20 ml. This solution containing the chloramine was added dropwise to 60 ml. of 99.5% phosphoric acid. The cosolvent was evaporated and the viscous mixture stirred at 20 for 4 hours. The mixture was diluted with water and made alkaline with 6N sodium hydroxide. The alkaline phase was allowed to reach about 40, and was extracted with ether. The ethereal phase was dried over anhydrous potassium carbonate and concentrated to dryness. The product (12.8 g.) was absorbed on 100 g. of neutral alumina, activity [1. Elution with benzene and dichloromethane yielded 9.2 g. (65%) of an amorphous mixture comprising racemic 6,7'-dimethoxydihydrocinchonidinone and racemic 6',7'-dimethoxydihydrocinchoninone.

EXAMPLE 24 Preparation of Racemic 6,7-Dimethoxydihydrocinchonidine and Racemic 6,7'-Dimethoxydihydrocinchonine from a mixture of racemic 6',7'-Dimethoxydihydrocinchonidinone and Racemic 6',7-Dimethoxydihydrocinchoninone To a solution containing 9.2 g. of a mixture of the racemic 6',7'-dimethoxydihydrocinchonidinone and racemic 6,7-dimethoxydihydrocinchoninone in 200 ml. of dry benzene, which was stirred under an atmosphere of dry nitrogen at 20, was added dropwise a 25% solution of di-isobutyl aluminum hydride in toluene. After the addition of 17.5 ml., the reaction was completed. The reaction was quenched by addition of 40 ml. of methanol-water (3:2). The precipitated alumina was separated by filtration and washed thoroughly with benzene. The filtrates were combined. The benzene layer was separated, dried over anhydrous sodium sulfate and evaporated to dryness. The product was separated by preparative thin layer chromatography (silica gel GF chloroform-triethylamine-methanol,

: 10:5). The less polar fraction yielded 4.4g. of amorphous, racemic 6',7'-dimethoxydihydrocinchonine.

For final purification, the base was converted to the racemic 6',7-dimethoxydihydrocinchonine dihydrochloride, which had a melting point of 221225 (dec.) after recrystallization from methanol.

The more polar fraction (3.4 g.) containing racemic 6',7'-dimethoxydihydrocinchonidine gave crystals from acetone having a melting point of l55l57. Racemic 6',7-dimethoxydihydrocinchonidine dihydrochloride was obtained after recrystallization from methanol and had a melting point of 208-2l0 (dec.).

EXAMPLE 25 Rac. cis 1-chloro-3-ethyl-4-piperidinepropionic acid ethyl ester.

A. To a solution of 1.064 g of racemic cis 3-ethyl-4- piperidinepropionic acid ethyl ester in 30 ml. of ether was added 30 ml. ofa 16.9 percent aqueous solution of sodium hypochlorite. The mixture was shaken at room temperature. In intervals of 1 hour the aqueous layer was separated and fresh sodium hypochlorite solution (30 ml.) was added. After 4.5 hours, ml. of benzene was added to the mixture. The organic layer was separated and washed successively with water (2 x), 3N aqueous hydrochloric acid (3 x) and water (3 x). After drying over sodium sulfate and evaporating under reduced pressure 0.90 g. ofliquid racemic cis l-chloro-3- ethyl-4-piperidinepropionic acid ethyl ester was obtained.

B. To a stirred suspension of 11 g. of N- chlorosuccinimide in 200 ml. of anhydrous ether was added in a nitrogen atmosphere a solution of 15 g. of racemic cis 3-ethyl-4-piperidinepropionic acid ethyl ester in 100 ml. of anhydrous ether. After continued stirring for 1 hour at room temperature the mixture was successively washed with water (3 x), 2.5N aqueous sulfuric acid (2 x) and water. The ethereal solution was dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure gave 18 g. of liquid racemic cis l-chloro-3-ethyl-4-piperidinepropionic acid ethyl ester.

EXAMPLE 26 Rac. cis l-benzoyl-3-(2-chloroethyl)-4- piperidinepropionic acid ethyl ester.

Eighteen grams of racemic cis l-chloro-3-ethyl-4- piperidinepropionic acid ethyl ester was dissolved in ml. of trifluoroacetic acid at 0. The resulting clear solution was transferred to a quartz flask, purged with dry nitrogen for 30 minutes and then irradiated at 10 with 200W-Hanovia high-pressure mercury lamp. At intervals, samples were removed and the reaction was continued until a negative starch-iodide test was obtained. After 5 hours, the solvent was removed at 35 under reduced pressure. Benzene was added to the residue and evaporated under reduced pressure. This procedure was repeated several times. To a stirred solution of 40 g. of the crude racemic cis 3-(2-chloroethyl)-4- piperidinepropionic acid ethyl ester trifluoroacetate and 26 g. of benzoyl chloride in 400 ml. of benzene was added over a period of 2 hours a saturated aqueous solution of potassium carbonate until the pH reached 9. Stirring was continued for 1 hour. After the addition of 200 ml. of benzene, the mixture was washed successively with 6N aqueous sodium hydroxide (3 x) water, 3N aqueous hydrochloric acid and water. The organic layer was separated and dried over anhydrous sodium sulfate. Evaporation to dryness gave 30 g. of oily material, which was chromatographed on 650 g. of silica gel with benzeneethyl acetate (9:1) as the liquid phase to give 22.3 g. of 96.3 per cent pure of racemic cis 1- benzoyl-3-(2-chloroethyl)-4-piperidinepropionic acid ethyl ester. Yield 87 percent. 7

EXAMPLE 27 Rae. cis 1-Benzoyl-3-vinyl-4-piperidinepropionic acid ethyl ester.

A. A solution of 3.5 g of racemic cis 1-benzoyl-3-(2- chloroethyl)-4-piperidinepropionic acid ethyl ester and 2.3 g. of sodium iodide in 120 ml. of methyl ethyl ketone was kept at reflux temperature for 44 hours. The mixture in which a precipitate had formed was diluted with 50 ml. of water and 100 ml. of ether. The organic layer was separated, washed with water, diluted with a benzene (100 ml.), dried over anhydrous sodium sulfate, and evaporated to dryness to give 4 g. of liquid racemic cis l-benzoyl-3-(2-iodoethyl)-4- piperidinepropionic acid ethyl ester. This was dissolved in 120 ml. of anhydrous pyridine, and after the addition of 2.5 g. of silver fluoride, the mixture was stirred at room temperature for 24 hours. Ether (800 ml.) was added, and the black precipitate was removed by filtration. The filtrate was washed with 3N aqueous hydrochloric acid (3 x) and water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was distilled under a pressure of 0.015 mm Hg to give two fractions: at 120C. 0.615 g. of 82 percent pure and at 150C. 0.990 g. of 71 percent pure of liquid racemic cis l-benzoyl-3-vinyl-4-piperidinepropionic acid ethyl ester: yield 38 percent.

B. The mixture of 0.5 g. of racemic cis l-benzoyl-3- (2-chloroethyl)-4-piperidinepropionic acid ethyl ester and glass powder washeated at 190 under a pressure of 0.025 mm. for hours. The black reaction mixture was dissolved in dichloromethane. the glass powder was removed by filtration, and the filtrate was evaporated to dryness. The residue (350 mg.) was distilled at 0.015 mm. Hg and 150C., to give 99 mg. of liquid 78% pure rac. cis l-benzoyl- 3-vinyl-4-plperidinepropionic acid ethyl ester.

EXAMPLE 28 l-Benzoyl-3(S)-(2-chloroethyl)-4(S)- piperidinepropionic acid ethyl ester.

The mono-l-tartrate of 3(S)-ethyl-4(S)- piperidinepropionic acid ethyl ester (8.9 g.) was treated with excess 2N aqueous potassium carbonate. The liberated free base was extracted into dichloromethane. The combined organic extract was dried over potassium carbonate and evaporated to dryness under reduced pressure to give 5 g. of 3(S)-ethyl-4(S)- piperidinepropionic acid ethyl ester. A solution of the free base in 35 ml. of anhydrous ether was added in a nitrogen atmosphere to a stirred suspension of 3.4 g. of

N-chloro-succinimide in 70 ml. of anhydrous ether.

After continued stirring for 1 hour at room temperature, the mixture was successively washed with water (3x), 2.5N aqueous sulfuric acid (2 x) and water. The

ethereal solution was dried over anhydrous sodium sul-' fate. Evaporation of the solvent under reduced pressure gave 5.1g. of liquid l-chloro-3(S)-ethy|-4(S)- piperidinepropionic acid ethyl ester. This N- chloroamine was dissolved in 150 ml. of trifluoroacetic acid at 0. The resulting clear solution was transferred to a quartz flask, purged with dry nitrogen for 30 minutes and then irradiated at 14 with a 200W-Hanovia high-pressure mercury lamp. At intervals, samples were removed and the reaction was continued as long as positive starch-iodine test was obtained. After 3 hours the solvent was removed at 35 under reduced pressure. Benzene was added to the residue and evaporated under reduced pressure. This procedure was repeated several times. To a stirred solution of thus obtained 3(- S)-(2-chloroethyl)-4(S)-piperidinepropionic acid ethyl ester trifluoroacetate (11.9 g.) and 8g. of benzoylchloride in 100 ml. of benzene was added slowly a saturated aqueous solution of potassium carbonate until the mixture reached pH 9. Stirring was continued for minutes. After the addition of ml. of benzene, the mixture was washed successively with 6N aqueous sodium hydroxide (3 x), water, 3N aqueous hydrochloric acid and water. The organic layer was separated and dried over anhydrous sodium sulfate. Evaporation to dryness gave 8.4 g. of oily material which was chromatographed on 250 g. of silica gel. Elution with 95:5 9:1 and 99:2 mixtures of benzene and ethylacetate gave 5.95 g. of liquid 87 percent pure l-benzoyl-3(S)-(2- chloroethyl)-4(S)-piperidinepropionic acid ethyl ester. Yield 60 percent. This product was distilled twice at 0.015 mmHg and C, to give 2 g. of 98.9 percent pure l-benzoyl-3(S)-(2-chloroethyl)-4(S)- piperidinepropionic acid ethyl ester [a]th D 20,0 (c 0,99, methanol).

EXAMPLE 29 l-Benzoyl-3(S)-vinyl-4(S)-piperidinepropionic acid ethyl ester.

A. solution of 1.9 g. of l-benzoyl-3(S)-(2- chloroethyl)-4(S)-piperidinepropionic acid ethyl ester and 1.22 g. of sodium iodide in 60 ml. of methyl ethyl ketone was kept at reflux temperature for 50 hours. The mixture in which a precipitate had formed wasdiluted with 30 ml. of water and 50 ml. of ether. The organic layer was separated, washed with water diluted with benzene (50 ml.), dried over anhydrous sodium sulfate, and evaporated to dryness to give 22 g. of liquid crude 1-benzoyl-3(S)-(2-iodoethyl)-4(S)- piperidinepropionic acid ethyl ester. This was dissolved in 60 ml. of anhydrous pyridine, and after the addition of 1.3 g. of silver fluoride, the mixture was stirred at room temperature for 20 hours. Ether (400 ml.) was added and the black precipitate was removed by filtration. The filtrate was washed with 3N aqueous hydrochloric acid (3 x) and water, dried over anhydrous sodium sulfate and evaporated to dryness. The liquid resi due (0.82 g.) was distilled at 0.015 mmHg and 118C. to give 540 mg. of 75 percent pure 1-benzoyl-3(S)- vinyl-4(S)-piperidinepropionic acid ethyl ester.

EXAMPLE 30 l-Benzoyl-3(R)-(2-chloroethyl)-4(R)- piperidinepropionic acid ethyl ester.

The mono-d-tartrate of 3(R)-ethyl-4(R)- piperidinepropionic acid ethyl ester (15 g.) was treated with excess 2N aqueous potassium carbonate. The liberated free base was extracted into dichloromethane. The combined organic extract was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to give 8.8 g. of 3(R)-ethyl-4(R)- piperidinepropionic acid ethyl ester. A solution of the free base in 60 ml. of anhydrous ether was added in a nitrogen atmosphere to a stirred suspension of 6.0 g. of N-chlorosuccinimide in 120 ml. of anhydrous ether. After continued stirring for 1 hour at room temperature, the mixture was successively washed with water (3 x), 2.5 N aqueous sulfuric acid (2 x) and water. The ethereal solution was dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure gave 9 g. of liquid 1-chloro-3(R)-ethyl-4(R)- piperidinepropionic acid ethyl ester. This N- chloroamine was dissolved in 150 ml. of trifluoroacetic acid at The resulting clear solution was transferred to a quartz flask, purged with dry nitrogen for 30 minutes and then irradiated at 10 with 200W-Hanovia high pressure mercury lamp. At intervals, samples were removed and the reaction was continued as long as a positive starch-iodine test was obtained. After 5 hours, the solvent was removed at 35 under reduced pressure. Benzene was added to the residue and evaporated under reduced pressure. This procedure was repeated several times. To a stirred solution of 3(R)-(2- chloroethyl)-4(R)-piperidinepropionic acid ethyl ester trifluoroacetate (22g) thus obtained and g. of benzoylchloride in 150 ml. of benzene was added slowly a saturated aqueous solution of potassium carbonate until the mixture reached pH 9. Stirring was continued for 1 hour. After the addition of 200 ml. of benzene, the mixture was washed successively with 6N aqueous sodium hydroxide (3x), water, 3N aqueous hydrochloric acid and water. The organic layer was separated and dried over anhydrous sodium sulfate. Evaporation to dryness gave 18 g. of oily material which was chromatographed on 650 g. of silica gel. Elution with 9:1 mixture of benzene and ethyl acetate gave 11.1 g. of liquid 97.5 percent pure 1-benzoyl-3(R)-(2- chloroethyl)-4(R)-piperidinepropionic acid ethyl ester. Yield 74 percent. Analytical sample of 98.6 percent purity was obtained by distillation at 0.018 mmHg and 150C. [a] =+20.2 (c 1.09, methanol).

EXAMPLE 31 1-Benzoyl-3(R)-vinyl-4(R)-piperidinepropionic ethyl ester A solution of 1.8 g. of 1-benzoyl-3(R)-(2- chloroethyl)-4(R)-piperidinepropionic acid ethyl ester and 1.2 g. of sodium iodide in 60 ml. of methyl ketone was kept at reflux temperature for 44 hours. The mixture in which a precipitate had formed was diluted with 30 ml. of water and 50 ml. of ether. The organic layer was separated, washed with water, diluted with benzene (50 ml.), dried over anhydrous sodium sulfate and evaporated to dryness to give 2.3 g. of liquidcrude 1- benzoyl-3(R)-(2-iodoethyl)-4(R)-piperidinepropionic acid ethyl ester. This was dissolved in 60 ml. of anhydrous pyridine, and after the addition of 1.29 g. of silver fluoride the mixture was stirred at room temperature for 15 hours. Ether (400 ml.) was added and the black precipitate was removed by filtration. The filtrate was washed with 3N aqueous hydrochloric acid (3x) and water, dried over anhydrous sodium sulfate and evaporated to dryness. The liquid residue (1.23 g.) was distilled under a pressure of 0.015 mmHg. A fraction (560 mg.) distilling at 100 (oil bath temperature) contained 94 percent pure 1-benzoyl-3(R)-vinyl-4(R)- piperidinepropionic acid ethyl ester. By raising the oil bath temperature to 115, 320 mg. of a second fraction containing 87 percent pure 1-benzoyl-3(R)-vinyl-4(R)- acid piperidinepropionic acid ethyl ester was obtained. Total yield 50 percent.

EXAMPLE 32 Preparation of 7-chlorodihydrocinchonine from 7- chlorocinchonine To a solution of 1.06 g. of 7-chlorocinchonine (as dihydrochloride monohydrate) in 500 ml. of methanol was added 2.5 ml. of 99 percent hydrazine hydrate and ca. 10 mg. of cupric sulfate and the mixture was stirred at room temperature in an open flask for two days. The methanol was evaporated. the residue partitioned between water and chloroform containing 5 percent of ethanol, the organic phase was washed (water), dried (sodium sulfate) and evaporated to give 0.8 g. of crude product. Crystallization from ethanol-tetrahydrofuran afforded 0.743 g. of 7'-chlorodihydrocinchonine; m.p. 278-279 [a] =+l59.7 (c 0.73 in ethanol-acetic acid 9:1

EXAMPLE 32a 6-Chlorodihydrocinchonidine chlorocinchonidine To a solution of 2.39 g. of 6-chlorocinchonidine in 100 ml. of absolute methanol was added 1.5 g. of 99 percent hydrazine hydrate (4 molar equivalents) and about 20 mg. of cupric acetate. The mixture was stirred in an open flask at 20 for 3 days, filtered through celite, the filtrate evaporated and the crude product was crystallized from acetonitrile to give 1.9 g. of crystalline 6'-chlorodihydrocinchonidine; after recrystallization from acetonitrile: mp 196-197; [(11 1 119 (c 0.94, methanol). Dihydrochloride. crystallized from ethanol-acetone: mp 215216(dec.); [11],, 115 (c 1.02, methanol).

EXAMPLE 32b 6-Chlorodihydrocinchonine from 6'-chlorocinchonine To a solution of 1.3 g. of 6-chlorocinchonine in 50 ml. of absolute methanol was added 0.8 g. of 99 percent hydrazine hydrate (4 molar equivalents) and about 10 mg. of cupric acetate. The mixture was stirred in an open flask for 3 days at 20, filtered through celite, the filtrate was evaporated, and the crude product crystallized from acetone. The first crop (0.4 g.) was combined with mother liquors purified by prep. layer chromatography and recrystallized from acetone to give 0.94 g. (about 72 percent yield) of 6'- chlorodihydrocinchonine; mp 98100; [a],, 185.2 (c 1.0, methanol); dihydrochloride, crystallized from ethanol-acetone as three quarter hydrate: mp 172174; [011, 171 (c 0.94, methanol).

EXAMPLE 33 Preparation of Racemic 6-Chlorodihydrocinchotoxine from 6'- I from cis (1-benzoyl-3-ethyl-4-piperidinepropionic acid ethyl ester and 6-chloro-4-carbethoxyquinoline A solution containing 25.4 g. of cis (1-benzoyl-3- ethyl-4-piperidinepropionic acid ethyl ester in 250 ml. of dry tetrahydrofuran was added dropwise (30 min.) to a refluxing mixture of 26.9 g. of potassium tbutoxide and 19.0 g. of 6-chloro-4-carbethoxyquinoline under an atmosphere of dry nitrogen. The mixture was heated under reflux for two hours, and the solvent was removed under reduced pressure. The cold residue was dissolved in 300 ml. of 0.5N sodium hydroxide, and washed with four 50 ml. portions of benzene. The combined aqueous phases containing the B-ketoester were acidified (conc. HCl whereby a 6N hydrochloric acid solution was obtained, and then heated under reflux for hours. The cooled reaction mixture was made alkaline with 6N sodium hydroxide, and extracted with EXAMPLE 34 Preparation of a Mixture of racemic 6'- Chlorodihydrocinchonidinone and Racemic 6- chlorodihydrocinchoninone from Racemic 6- Chlorodihydrocinchotoxine To a solution containing 13.6 g. of racemic 6'- chlorodihydrocinchotoxine in 200 ml. of dichloromethane was added 18 ml. of about a 17% aqueous sodium hypochlorite and the mixture was stirred for 60 min. The organic phase was separated, washed with water, dried over anhydrous sodium sulfate and concentrated to a volume of about 20 ml. This solution, containing the chloramine, was added dropwise to 60 ml. of 99.5% phosphoric acid. The solvent was evaporated, and the viscous mixture was stirred at 20 for 17 hours. The mixture was diluted with water, and made alkaline with 6N potassium hydroxide. The alkaline aqueous phase was kept at about 70 for 30 min., and, thereafter, it was extracted thoroughly with ether. The ethereal phase was dried over anhydrous potassium carbonate and concentrated to dryness. The product l 1.7 g.) was absorbed on 100 g. of neutral alumina, activity 11. Elution with benzene and dichloromethane yielded 9.3 g. (69%) of racemic 6-chlorodihydrocinchonidinone and racemic 6-chlorodihydrocinchoninone which was crystallized from hexaneto give 7.56 g. of a product having a melting point of 97.5-l00.5 containing some chlorine free impurity. A crystalline mixture of racemic 6-chlorodihydrocinchonidinone and racemic 6- chlorodihydrocinchoninone was prepared also by reoxidizing a mixture of racemic 6- chlorodihydrocinchonine and racemic 6- chlorodihydrocinchonidine.

EXAMPLE 35 Preparation of Racemic 6'-Chlorodihydrocinchonidine and Racemic 6-Chlorodihydrocinchonine from a mixture of Racemic 6'-Chlorodihydrocinchonidinone and Racemic 6-Chlorodihydrocinchoninone To a solution of 6.73 g. of a mixture of the racemic 6'-chlorodihydrocinchonidinone and racemic 6'- chlorodihydrocinchoninone (material melting at 97.5-l00) in 200 ml. ofdry benzene, stirred under an atmosphere of dry nitrogen at 20, was added dropwise a percent solution of di-isobutyl alumina hydride in toluene. After addition of l 3 ml., the reaction was completed. The reaction was quenched by addition of 20 ml. of methanol-water (2:3). The precipitated alumina was separated by filtration and washed thoroughly with benzene. The filtrates were combined. The benzene layer was separated and dried over anhydrous sodium sulfate and evaporated to dryness. The product (6.7 g.) could not be crystallized; therefore, it was separated by preparative thin layer chromatography (silica gel GE 254; chloroform-triethylamine=9:l) into three fractions.

The least polar fraction l .34 g.) was crystallized and recrystallized from acetone to give racemic 6- chlorodihydrocinchonine having a melting point of l72.5l73.5. Racemic 6-chlorodihydrocinchonine dihydrochloride had a melting point of 2l822l (dec.).

The middle fraction (2.83 g.) was crystallized from acetone to give racemic 6'-chlorodihydrocinchonidine having a melting point of 102.

Racemic 6'-chlorodihydrocinchonidine dihydrochloride had a melting point of 2l9222 (dec.) (recrystallized from methanolether).

EXAMPLE 36 Preparation of Racemic 6'-Methyldihydrocinchotoxine from cis (1-benzoyl-3-ethyl-4-piperidinepropionic acid ethyl ester and 6-methyl-4-carbethoxyquinoline A solution containing 19.6 g. of cis (l-benzoyl-3- ethyl-4-piperidinepropionic acid ethyl ester in 600 ml. of dry benzene was added dropwise (3- /2 hours) to a refluxing mixture comprising 20.3 g. of 6-methyl-4-carbethoxyquinoline and 20.8 g. of potassium t-butoxide in 300 ml. of dry benzene under an atmosphere of dry nitrogen. The mixture was heated under reflux for an additional hour and maintained at 20 overnight. The crude mixture was extracted once with 200 ml. and three times with 20 ml. of cold 0.5N aqueous potassium hydroxide. Thereafter, the aqueous phases were washed with 4 portions of 50 ml. of benzene. The combined alkaline aqueous phases containing the crude B-ketoester were acidified with cone. l-lCl whereby a 6N hydrochloric acid solution was obtained, and then heated under reflux for 24 hours. The cooled mixture was made alkaline with 6N potassium hydroxide, and extracted with ether. The ethereal extracts were dried over anhydrous potassium carbonate and evaporated to dryness to give 13.1 g. (68%) of racemic 6'-methyldihydrocinchotoxine.

EXAMPLE 37 Preparation of a Mixture of racemic 6-Methyl- 6'-methyl-dihydrocinchotoxine in ml. of dichloromethane was added an excess of about 17% aqueous sodium hypochlorite solution, and the mixture was stirred at 20 for 1 hour. The organic phase was separated, washed with water, dried over anhydrous sodium sulfate and concentrated to 20 ml. This solution, containing the chloramine, was added dropwise to 50 ml. of 99.5% phosphoric acid. The dichloromethane was evaporated. and the viscous mixture was stirred at 20 for 17 hours. Thereafter, the mixture was diluted with 20 ml. of water and made alkaline with 6N potassium hydroxide. The alkaline aqueous phase was maintained at 40 for 30 min., and subsequently extracted with dichloromethane. The organic extracts were dried over anhydrous sodium sulfate and concentrated to dryness to give 13.2 g. of a crystalline product. A portion was recrystallized twice from hexane to give about a 1:1 mixture of 6'-methyl-dihydrocinchonidinone and racemic 6'methyl-dihydrocinchoninone having a melting point of l05l08. 

1. A COMPOUND OF THE FORMULA
 2. A compound in accordance with claim 1, wherein R2 is lower alkyl.
 3. A compound in accordance with claim 2, Alpha -(1-benzoyl-3(R)-ethyl-4(R)-piperidylmethyl)- Beta -oxo- Beta -(7-methoxy-4-quinolyl)-propionic acid ethyl ester.
 4. A compound in accordance with claim 2, racemic Alpha -(1-benzoyl-3(R)-ethyl-4-(R)-piperidylmethyl)- Beta -oxo- Beta -(7-methoxy-4-quinolyl)-propionic acid ethyl ester.
 5. A compound in accordance with claim 2, racemic Alpha -(1-benzoyl-3(R)-ethyl-4(R)-piperidylmethyl)- Beta -oxo- Beta -(6-chloro-4-quinolyl)-propionic acid ethyl ester.
 6. A compound in accordance with claim 2, racemic Alpha -(1-benzoyl -3(R)-ethyl-4(R) -piperidylmethyl)- Beta -oxo- Beta -(6-methyl-4-quinoyl)-propionic acid ethyl ester.
 7. A compound in accordance with claim 2, racemic Alpha -cis1-benzoyl-3-ethyl-4-piperidylmethyl)- Beta -oxo- Beta -(7-methyl-4-quinolyl)-propionic acid ethyl ester.
 8. A compound in accordance with claim 2, Alpha -(1-benzoyl-3(R)-ethyl-4(R)-piperidylmethyl)- Beta -oxo- Beta -(6,7-dimethoxy-4-quinolyl)-propionic acid ethyl ester.
 9. A compound in accordance with claim 2, racemic Alpha -(1-benzoyl-3(R)-ethyl-4(R)-piperidylmethyl)- Beta -oxo- Beta -(6,7-dimethoxy-4-quinolyl)-propionic acid ethyl ester. 